Broadspectrum 2-(substituted-amino)-benzoxazole sulfonamide hiv protease inhibitors

ABSTRACT

The present invention concerns the compounds having the formula  
                 
 
     N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein R 1  and R 8  each are H, optionally substituted C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, aryl, Het 1 , Het 2 ; R 1  may also be a radical of formula (R 11a R 11b )NC(R 10a R 10b )CR 9 —; t is 0, 1 or 2; R 2  is H br C 1-6 alkyl; L is —C(═O)—, —O—C(═O)—, —NR 8 —C(═O)—, —C 1-6 alkanediyl-C(═O)—, —NR 8 —C 1-6 alkanediyl-C(═O)—, —S(═O) 2 —, —O—S(═O) 2 —, —NR 8 —S(═O) 2 ; R 3  is C 1-6 alkyl, aryl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, or arylC 1-4 alkyl; R 4  is H, C 1-4 alkylOC(═O), carboxyl, aminoC(═O), mono- or di(C 1-4 alkyl)aminoC(═O), C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or optionally substituted C 1-6 alkyl; A is C 1-6 alkanediyl, —C(═O)—, —C(═S)—, —S(═O) 2 —, C 1-6 alkanediyl-C(═O)—, C 1-6 alkanediyl-C(═S)—or C 1-6 alkanediyl-S(═O) 2 —; R 5  is H, OH, C 1-6 alkyl, Het 1 C 1-6 alkyl, Het 2 C 1-6 alkyl, optionally substituted aminoC 1-6 alkyl; R 6  is C 1-6 alkylO, Het 1 , Het 1 O, Het 2 , Het 2 O, aryl, arylO, C 1-6 alkyloxycarbonylamino or amino; and in case -A- is other than C 1-6 alkanediyl then R 6  may also be C 1-6 alkyl, Het 1 C 1-4 alkyl, Het 1 OC 1-4 alkyl, Het 2 C 1-4 alkyl, Het 2 OC 1-4 alkyl, arylC 1-4 alkyl, arylOC 1-4 alkyl or aminoC 1-4 alkyl; whereby each of the amino groups in the definition of R 6  may optionally be substituted; -A-R 6  is hydroxyC 1-6 alkyl; R 5  and -A-R 6  taken together with the nitrogen atom to which they are attached may also form Het 1  or Het 2 . It further relates to their use as broadspectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. It also concerns combinations thereof with another anti-retroviral agent, and to their use in assays as reference compounds or as reagents.

[0001] The present invention relates to2-(substituted-amino)-benzoxazole sulfonamides, their use as asparticprotease inhibitors, in particular as broadspectrum HIV proieaseinhibitors, processes for their preparation as well as pharmaceuticalcompositions and diagnostic kits comprising them. The present inventionalso concerns combinations of the present2-(substituted-amino)-benzoxazole sulfonamides with anotheranti-retroviral agent. It further relates to their use in assays asreference compounds or as reagents.

[0002] The virus causing the acquired immunodeficiency syndrome (AIDS)is known by different names, including T-lymphocyte virus III (HTLV-III)or lymphadenopathy-associated virus (LAV) or AIDS-related virus (ARV) orhuman immunodeficiency virus (HIV). Up until now, two distinct familieshave been identified, i.e. HIV-1 and HIV-2. Hereinafter, HIV will beused to generically denote these viruses.

[0003] One of the critical pathways in a retroviral life cycle is theprocessing of polyprotein precursors by aspartic protease. For instancewith the HIV virus the gag-pol protein is processed by HIV protease. Thecorrect processing of the precursor polyproteins by the asparticprotease is required for the assembly of infectious virions, thus makingthe aspartic protease an attractive target for antiviral therapy. Inparticular for HIV treatment, the HIV protease is an attractive target.

[0004] HIV protease inhibitors (PIs) are commonly administered to AIDSpatients in combination with other anti-HIV compounds such as, forinstance nucleoside reverse transcriptase inhibitors (NRTIs),non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotidereverse transcriptase inhibitors (NtRTIs) or other protease inhibitors.Despite the fact that these antiretrovirals are very useful, they have acommon limitation, namely, the targeted enzymes in the HIV virus areable to mutate in such a way that the known drugs become less effective,or even ineffective against these mutant HIV viruses. Or, in otherwords, the HIV virus creates an ever increasing resistance against theavailable drugs.

[0005] Resistance of retroviruses, and in particular the HIV virus,against inhibitors is a major cause of therapy failure. For instance,half of the patients receiving anti-HIV combination therapy do notrespond fully to the treatment, mainly because of resistance of thevirus to one or more drugs used. Moreover, it has been shown thatresistant virus is carried over to newly infected individuals, resultingin severely limited therapy options for these drug-naive patients.Therefore, there is a need in the art for new compounds for retrovirustherapy, more particularly for AIDS therapy. The need in the art isparticularly acute for compounds that are active not only on wild typeHIV virus, but also on the increasingly more common resistant HIVviruses.

[0006] Known antiretrovirals, often administered in a combinationtherapy regimen, will eventually cause resistance as stated above. Thisoften may force the physician to boost the plasma levels of the activedrugs in order for said antiretrovirals to regain effectivity againstthe mutated HIV viruses. The consequence of which is a highlyundesirable increase in pill burden. Boosting plasma levels may alsolead to an increased risk of non-compliance with the prescribed therapy.Thus, it is not only important to have compounds showing activity for awide range of HIV mutants, it is also important that there is little orno variance in the ratio between activity against mutant HIV virus andactivity against wild type HIV virus (also defined as fold resistance orFR) over a broad range of mutant HIV strains. As such, a patient mayremain on the same combination therapy regimen for a longer period oftime since the chance that a mutant HIV virus will be sensitive to theactive ingredients will be increased.

[0007] Finding compounds with a high potency on the wild type and on awide variety of mutants is also of importance since the pill burden canbe reduced if therapeutic levels are kept to a minimum. One way ofreducing this pill burden is finding anti-HIV compounds with goodbioavailability, i.e. a favorable pharmacokinetic and metabolic profile,such that the daily dose can be minimized and consequently also thenumber of pills to be taken.

[0008] Another important characteristic of a good anti-HIV compound isthat plasma protein binding of the inhibitor has minimal or even noeffect on its potency.

[0009] Thus, there is a high medical need for protease inhibitors thatare able to combat a broad spectrum of mutants of the HIV virus withlittle variance in fold resistance, have a good bioavailability andexperience little or no effect on their potency due to plasma proteinbinding.

[0010] Up until now, several protease inhibitors are on the market orare being developed. One particular core structure (depicted below) hasbeen disclosed in a number of references, such as, WO 95/06030, WO96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO97/18205. The compounds disclosed therein are described as retroviralprotease inhibitors.

[0011] WO 99/67254 discloses 4-substituted-phenyl sulfonamides capableof inhibiting multi-drug resistant retroviral proteases.

[0012] Surprisingly, the 2-(substituted-amino)-benzoxazole sulfonamidesof the present invention are found to have a favorable pharmacologicaland pharmacokinetic profile. Not only are they active against wild-typeHIV virus, but they also show a broadspectrum activity against variousmutant HIV viruses exhibiting resistance against known proteaseinhibitors.

[0013] The present invention concerns 2-(substituted-amino)-benzoxazoleprotease inhibitors, having the formula

[0014] and N-oxides, salts, stereoisomeric forms, racemic mixtures,prodrugs, esters and metabolites thereof, wherein

[0015] R₁ and R₈ are, each independently, hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, arylC₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl,aryl, Het¹, Het¹C₁₋₆alkyl, Het², Het²C₁₋₆alkyl;

[0016] R₁ may also be a radical of formula

[0017]  wherein

[0018] R₉, R_(10a) and R_(10b) are, each independently, hydrogen,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl orC₁₋₄alkyl optionally substituted with aryl, Het¹, Het², C₃₋₇cycloalkyl,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(O)_(t), hydroxy,cyano, halogen or amino optionally mono- or disubstituted where thesubstituents are each independently selected from C₁₋₄alkyl, aryl,arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het²,Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl; whereby R₉, R_(10a) and the carbon,atoms to which they are attached may also form a C₃₋₇cycloalkyl radical;when L is —O—C₁₋₆alkanediyl-C(═O)— or —NR₈—C₁₋₆alkanediyl-C(═O)—, thenR₉ may also be oxo;

[0019] R_(11a) is hydrogen, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl,aryl, aminocarbonyl optionally mono- or disubstituted,aminoC₁₋₄alkylcarbonyloxy optionally mono- or disubstituted,C₁₋₄alkyloxycarbonyl, aryloxycarbonyl, Het¹oxycarbonyl, Het²oxycarbonyl,aryloxycprbonylC₁₋₄alkyl, arylC₁₋₄alkyloxycarbonyl, C₁₋₄alkylcarbonyl,C₃₋₇cycloalkylcarbonyl, C₃₋₇cycloalkyl-C₁₋₄alkyloxycarbonyl,C₃₋₇cycloalkylcarbonyloxy, carboxylC₁₋₄alkylcarbonyloxy,C₁₋₄alkylcarbonyloxy, arylC₁₋₄alkylcarbonyloxy, arylcarbonyloxy,aryloxycarbonyloxy, Het¹carbonyl, Het¹carbonyloxy,Het¹C₁₋₄alkyloxycarbonyl, Het²carbonyloxy, Het²C₁₋₄alkylcarbonyloxy,Het²C₁₋₄alkyloxycarbonyloxy or C₁₋₄alkyl optionally substituted witharyl, aryloxy, Het², halogen or hydroxy; wherein the substituents on theamino groups are each independently selected from C₁₋₄alkyl, aryl,arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het²,Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl;

[0020] R_(11b) is hydrogen, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,aryl, Het¹, Het² or C₁₋₄alkyl optionally substituted with halogen,hydroxy, C₁₋₄alkylS(═O)t, aryl, C₃₋₇cycloalkyl, Het¹, Het², aminooptionally mono- or disubstituted where the substituents are eachindependently selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl;

[0021] whereby R_(11b) may be linked to the remainder of the moleculevia a sulfonyl group;

[0022] each independently, t is zero, 1 or 2;

[0023] R₂ is hydrogen or C₁₋₆alkyl;

[0024] L is —C(═O)—, —O—C(═O)—, —NR₈—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—,—NR₈—C₁₋₆alkanediyl-C(═O)—, —S(═O)₂—, —O—S(═O)₂—, —NR₈—S(═O)₂ wherebyeither the C(═O) group or the S(═O)₂ group is attached to the NR₂moiety; whereby the C₁₋₆alkanediyl moiety is optionally substituted witharyl, Het¹, Het²,

[0025] R₃ is C₁₋₆alkyl, aryl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl,or arylC₁₋₄alkyl;

[0026] R₄ is hydrogen, C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, or C₁₋₆alkyl optionally substituted with one or moresubstituents each independently selected from aryl, Het¹, Het²,C₃₋₇cycloalkyl, C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(═O)_(t), hydroxy,cyano, halogen and amino optionally mono- or disubstituted where thesubstituents are each independently selected from C₁₋₄alkyl, aryl,arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het²,Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl;

[0027] A is C₁₋₆alkanediyl, —C(═O)—, —C(═S)—, —S(═O)₂—,C₁₋₆alkanediyl-C(═O)—, C₁₋₆alkanediyl-C(═S)— or C₁₋₆alkanediyl-S(═O)₂—;whereby the point of attachment to the nitrogen atom is theC₁₋₆alkanediyl group in those moieties containing said group;

[0028] R₅ is hydrogen, hydroxy, C₁₋₆alkyl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,aminoC₁₋₆alkyl whereby the amino group may optionally be mono- ordi-substituted with C₁₋₄alkyl;

[0029] R₆ is C₁₋₆alkyloxy, Het¹, Het¹oxy, Het², Het²oxy, aryl, aryloxyor amino; and in case -A- is other than C₁₋₆alkanediyl then R₆ may alsobe C₁₋₆alkyl, Het¹C₁₋₄alkyl, Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl,Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl, aryloxyC₁₋₄alkyl or aminoC₁₋₆alkyl;whereby each of the amino groups in the definition of R₆ may optionallybe substituted with one or more substituents each independently selectedfrom C₁₋₄alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, aryl,arylcarbonyl, aryloxycarbonyl, Het¹, Het², arylC₁₋₄alkyl, Het¹C₁₋₄alkylor Het²C₁₋₄alkyl; and

[0030] -A-R₆ may also be hydroxyC₁₋₆alkyl;

[0031] R₅ and -A-R₆ taken together with the nitrogen atom to which theyare attached may also form Het¹ or Het².

[0032] This invention also envisions the quaternization of the nitrogenatoms of the present compounds. A basic nitrogen can be quaternized withany agent known to those of ordinary skill in the art including, forinstance, lower alkyl halides, dialkyl sulfates, long chain halides andaralkyl halides.

[0033] Whenever the term “substituted” is used in defining the compoundsof formula (I), it is meant to indicate that one or more hydrogens onthe atom indicated in the expression using “substituted” is replacedwith a selection from the indicated group, provided that the indicatedatom's normal valency is not exceeded, and that the substitution resultsin a chemically stable compound, i.e. a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and formulation into a therapeutic agent.

[0034] As used herein, the term “halo” or “halogen” as a group or partof a group is generic for fluoro, chloro, bromo or iodo.

[0035] The term “C₁₋₄alkyl” as a group or part of a group definesstraight and branched chained saturated hydrocarbon radicals having from11 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyland 2-methyl-propyl, and the like.

[0036] The term “C₁₋₆alkyl” as a group or part of a group definesstraight and branched chained saturated hydrocarbon radicals having from1 to 6 carbon atoms such as the groups defined for C₁₋₄alkyl and pentyl,hexyl, 2-methylbutyl, 3-methylpentyl and the like.

[0037] The term “C₁₋₆alkanediyl” as a group or part of a group definesbivalent straight and branched chained saturated hydrocarbon radicalshaving from 1 to 6 carbon atoms such as, for example, methylene,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,pentan-1,5-diyl, hexan-1,6-diyl, 2-methylbutan-1,4-diyl,3-methylpentan-1,5-diyl and the like.

[0038] The term “C₂₋₆alkenyl” as a group or part of a group definesstraight and branched chained hydrocarbon radicals having from 2 to 6carbon atoms containing at least one double bond such as, for example,ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.

[0039] The term “C₂₋₆alkynyl” as a group or part of a group definesstraight and branched chained hydrocarbon radicals having from 2 to 6carbon atoms containing at least one triple bond such as, for example,ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

[0040] The term “C₃₋₇cycloalkyl” as a group or part of a group isgeneric to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl.

[0041] The term “aryl” as a group or part of a group is meant to includephenyl and naphtyl which both may be optionally substituted with one ormore substituents independently selected from C₁₋₆alkyl, optionallymono- or disubstituted aminoC₁₋₆alkyl, C₁₋₆alkyloxy, halogen, hydroxy,optionally mono- or disubstituted amino, nitro, cyano, haloC₁₋₆alkyl,carboxyl, C₁₋₆alkoxycarbonyl, C₃₋₇cycloalkyl, Het¹, optionally mono- ordisubstituted aminocarbonyl, methylthio, methylsulfonyl, and phenyloptionally substituted with one or more substituents each independentlyselected from C₁₋₆alkyl, optionally mono- or disubstitutedaminoC₁₋₆alkyl, C₁₋₆alkyloxy, halogen, hydroxy, optionally mono- ordisubstituted amino, nitro, cyano, haloC₁₋₆alkyl, carboxyl,C₁₋₆alkoxycarbonyl, C₃₋₇cycloalkyl, Het¹, optionally mono- ordisubstituted aminocarbonyl, methylthio and metbylsulfonyl; whereby theoptional substituents on any amino function are independently selectedfrom C₁₋₆alkyl, optionally mono- or disubstituted aminoC₁₋₆alkyl,C₁₋₆alkyloxy-A-, Het¹-A-, Het¹C₁₋₆alkyl, Het¹C₁₋₆alkyl-A-, Het¹oxy-A-,Het¹oxyC₁₋₄akyl-A-, phenyl-A-, phenyl-oxy-A-, phenyloxyC₁₋₄alkyl-A-,phenyl-C₁₋₆alkyl-A-, C₁₋₆alkyloxycarbonylamino-A-, amino-A-,aminoC₁₋₆alkyl and amino-C₁₋₆alkyl-A-whereby each of the amino groupsmay optionally be mono- or where possible di-substituted with C₁₋₄alkyland whereby A is as defined above.

[0042] An interesting subgroup in the definition of “aryl” as a group orpart of a group includes phenyl and naphtyl which both may be optionallysubstituted with one or more substituents independently selected fromC₁₋₆alkyl, C₁₋₆alkyloxy, halogen, hydroxy, optionally mono- ordisubstituted amino, nitro, cyano, haloC₁₋₆alkyl, carboxyl,C₁₋₆alkoxycarbonyl, C₃₋₇cycloalkyl, Het¹, optionally mono- ordisubstituted aminocarbonyl, methylthio, methylsulfonyl, and phenyloptionally substituted with one or more substituents selected fromC₁₋₆alkyl, C₁₋₆alkyloxy, halogen, hydroxy, optionally mono- ordisubstituted amino, nitro, cyano, haloC₁₋₆alkyl, carboxyl,C₁₋₆alkoxycarbonyl, C₃₋₇cycloalkyl, Het¹, optionally mono- ordisubstituted aminocarbonyl, methylthio and methylsulfonyl; whereby theoptional substituents on any amino function are independently selectedfrom C₁₋₆alkyl, C₁₋₆alkyloxy-A-, Het¹-A-, Het¹C₁₋₆alkyl,Het¹C₁₋₆alkyl-A-, Het¹oxy-A-, Het¹oxyC₁₋₄akyl-A-, phenyl-A-,phenyl-oxy-A-, phenyloxyC₁₋₄alkyl-A-, phenylC₁₋₆alkyl-A-,C₁₋₆alkyloxycarbonyl-amino-A-, amino-A-, aminoC₁₋₆alkyl andaminoC₁₋₆alkyl-A- whereby each of the amino groups may optionally bemono- or where possible di-substituted with C₁₋₄alkyl and whereby A isas defined above.

[0043] The term “haloC₁₋₆alkyl” as a group or part of a group is definedas C₁₋₆alkyl substituted with one or more halogen atoms, preferably,chloro or fluoro atoms, more preferably fluoro atoms. PreferredhaloC₁₋₆alkyl groups include for instance trifluoromethyl anddifluoromethyl.

[0044] The term “Het¹” as a group or part of a group is defined as asaturated or partially unsaturated monocyclic, bicyclic or tricyclicheterocycle having preferably 3 to 14 ring members, more preferably 5 to10 ring members and more preferably 5 to 8 ring members, which containsone or more heteroatom ring members each independently selected fromnitrogen, oxygen or sulfur and which is optionally substituted on one ormore carbon atoms by C₁₋₆alkyl, optionally mono- or disubstitutedaminoC₁₋₆alkyl, C₁₋₆alkyloxy, halogen, hydroxy, oxo, optionally mono- ordisubstituted amino, nitro, cyano, haloC₁₋₆alkyl, carboxyl,C₁₋₆alkoxycarbonyl, C₃₋₇cycloalkyl, optionally mono- or disubstitutedaminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated orpartially unsaturated monocyclic, bicyclic or tricyclic heterocyclehaving 3 to 14 ring members which contains one or more heteroatom ringmembers each independently selected from nitrogen, oxygen or sulfur andwhereby the optional substituents on any amino function areindependently selected from C₁₋₆alkyl, optionally mono- or disubstitutedaminoC₁₋₆alkyl, C₁₋₆alkyloxy-A-, Het²-A-, Het²C₁₋₆alkyl,Het²C₁₋₆alkyl-A-, Het²oxy-A-, Het¹oxyC₁₋₁₄akyl-A-, aryl-A-, aryloxy-A-,aryloxyC₁₋₄alkyl-A-, arylC₁₋₆alkyl-A-, C₁₋₆alkyloxycarbonylamino-A-,amino-A-, aminoC₁₋₆alkyl and aminoC₁₋₆alkyl-A- whereby each of the aminogroups may optionally be mono- or where possible di-substituted withC₁₋₄alkyl and whereby A is as defined above. An interesting subgroup inthe definition of “Het¹” as a group or part of a group is defined as asaturated or partially unsaturated monocyclic, bicyclic or tricyclicheterocycle having preferably 3 to 12 ring members, more preferably 5 to10 ring members and more preferably 5 to 8 ring members, which containsone or more heteroatom ring members selected from nitrogen, oxygen orsulfur and which is optionally substituted on one or more carbon atomsby C₁₋₆alkyl, C₁₋₆alkyloxy, halogen, hydroxy, oxo, optionally mono- ordisubstituted amino, nitro, cyano, haloC₁₋₆alkyl, carboxyl,C₁₋₆alkoxycarbonyl, C₃₋₇cycloalkyl, optionally mono- or disubstitutedaminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated orpartially unsaturated monocyclic, bicyclic or tricyclic heterocyclehaving 3 to 12 ring members which contains one or more heteroatom ringmembers selected from nitrogen, oxygen or sulfur and whereby theoptional substituents on any amino function are independently selectedfrom C₁₋₆alkyl, C₁₋₆alkyloxy-A-, Het²-A-, Het²C₁₋₆alkyl,Het²C₁₋₆alkyl-A-, Het²oxy-A-, Het²oxyC₁₋₄akyl-A-, aryl-A-, aryloxy-A-,aryloxyC₁₋₄alkyl-A-, arylC₁₋₆alkyl-A-, C₁₋₆alkyloxycarbonylamino-A-,amino-A-, aminoC₁₋₆alkyl and aminoC₁₋₆alkyl-A- whereby each of the aminogroups may optionally be mono- or where possible di-substituted withC₁₋₄alkyl and whereby A is as defined above.

[0045] The term “Het²” as a group or part of a group is defined as anaromatic monocyclic, bicyclic or tricyclic heterocycle having preferably3 to 14 ring members, more preferably 5 to 10 ring members and morepreferably 5 to 6 ring members, which contains one or more heteroatomring members each independently selected from nitrogen, oxygen or sulfurand which is optionally substituted on one or more carbon atoms byC₁₋₆alkyl, optionally mono- or disubstituted aminoC₁₋₆alkyl,C₁₋₆alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino,nitro, cyano, haloC₁₋₆alkyl, carboxyl, C₁₋₆alkoxycarbonyl,C₃₋₇cycloalkyl, optionally mono- or disubstituted aminocarbonyl,methylthio, methylsulfonyl, aryl, Het¹ and an aromatic monocyclic,bicyclic or tricyclic heterocycle having 3 to 14 ring members; wherebythe optional substituents on any amino function are independentlyselected from C₁₋₆alkyl, optionally mono- or disubstitutedaminoC₁₋₆alkyl, C₁₋₆alkyloxy-A-, Het¹-A-, Het¹C₁₋₆alkyl,Het¹C₁₋₆alkyl-A-, Het¹oxy-A-, Het¹oxyC₁₋₄akyl-A-, aryl-A-, aryloxy-A-,aryloxyC₁₋₄alkyl-A-, arylC₁₋₆alkyl-A-, C₁₋₆alkyloxycarbonylamino-A-,amino-A-, aminoC₁₋₆alkyl and aminoC₁₋₆alkyl-A- whereby each of the aminogroups may optionally be mono- or where possible di-substituted withC₁₋₄alkyl and whereby A is as defined above.

[0046] An interesting subgroup in the definition of “Het²” as a group orpart of a group is defined as an aromatic monocyclic, bicyclic ortricyclic heterocycle having preferably 3 to 12 ring members, morepreferably 5 to 10 ring members and more preferably 5 to 6 ring members,which contains one or more heteroatom ring members selected fromnitrogen, oxygen or sulfur and which is optionally substituted on one ormore carbon atoms by C₁₋₆alkyl, C₁₋₆alkyloxy, halogen, hydroxy,optionally mono- or disubstituted amino, nitro, cyano, haloC₁₋₆alkyl,carboxyl, C₁₋₆alkoxycarbonyl, C₃₋₇cycloalkyl, optionally mono- ordisubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het¹ andan aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12ring members; whereby the optional substituents on any amino functionare independently selected from C₁₋₆alkyl, C₁₋₆alkyloxy-A-, Het¹-A-,Het¹C₁₋₆alkyl, Het¹C₁₋₆alkyl-A-, Het¹oxy-A-, Het¹oxyC₁₋₄akyl-A-,aryl-A-, aryloxy-A-, aryloxyC₁₋₄alkyl-A-, arylC₁₋₆alkyl-A-,C₁₋₆alkyloxycarbonylamino-A-, amino-A-, aminoC₁₋₆alkyl andaminoC₁₋₆alkyl-A-whereby each of the amino groups may optionally bemono- or where possible di-substituted with C₁₋₄alkyl and whereby A isas defined above.

[0047] As used herein, the term (═O) forms a carbonyl moiety with thecarbon atom to which it is attached. The term (═O) forms a sulfoxidewith the sulfur to which it is attached. The term (═O)₂ forms a sulfonylto the sulfur to which it is attached.

[0048] As used herein, the term (═S) forms a thiocarbonyl moiety withthe carbon atom to which it is attached.

[0049] As used herein before, the term “one or more” covers thepossibility of all the available C-atoms, where appropriate, to besubstituted, preferably, one, two or three.

[0050] When any variable (e.g. halogen or C₁₋₄alkyl) occurs more thanone time in any constituent, each definition is independent.

[0051] The term “prodrug” as used throughout this text means thepharmacologically acceptable derivatives such as esters, amides andphosphates, such that the resulting in vivo biotransformation product ofthe derivative is the active drug as defined in the compounds of formula(I). The reference by Goodman and Gilman (The Pharmacological Basis ofTherapeutics, 8^(th) ed, McGraw-Hill, Int. Ed. 1992. “Biotransformationof Drugs”, p 13-15) describing prodrugs generally is herebyincorporated. Prodrugs of a compound of the present invention areprepared by modifying functional groups present in the compound in sucha way that the modifications are cleaved, either in routine manipulationor in vivo, to the parent compound. Prodrugs include compounds of thepresent invention wherein a hydroxy group, for instance the hydroxygroup on the asymmetric carbon atom, or an amino group is bonded to anygroup that, when the prodrug is administered to a patient, cleaves toform a free hydroxyl or free amino, respectively.

[0052] Typical examples of prodrugs are described for instance in WO99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporatedherein by reference.

[0053] Prodrugs are characterized by excellent aqueous solubility,increased bioavailability and are readily metabolized into the activeinhibitors in vivo.

[0054] For therapeutic use, the salts of the compounds of formula (I)are those wherein the counterion is pharmaceutically or physiologicallyacceptable. However, salts having a pharmaceutically unacceptablecounterion may also find use, for example, in the preparation orpurification of a pharmaceutically acceptable compound of formula (I).All salts, whether pharmaceutically acceptable or not are includedwithin the ambit of the present invention.

[0055] The pharmaceutically acceptable or physiologically tolerableaddition salt forms which the compounds of the present invention areable to form can conveniently be prepared using the appropriate acids,such as, for example, inorganic acids such as hydrohalic acids, e.g.hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

[0056] Conversely said acid addition salt forms can be converted bytreatment with an appropriate base into the free base form.

[0057] The compounds of formula (I) containing an acidic proton may alsobe converted into their non-toxic metal or amine addition salt form bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl, -D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

[0058] Conversely said base addition salt forms can be converted bytreatment with an appropriate acid into the free acid form.

[0059] The term “salts” also comprises the hydrates and the solventaddition forms which the compounds of the present invention are able toform. Examples of such forms are e.g. hydrates, alcoholates and thelike.

[0060] The N-oxide forms of the present compounds are meant to comprisethe compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

[0061] The present compounds may also exist in their tautomeric forms.Such forms, although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

[0062] The term stereochemically isomeric forms of compounds of thepresent invention, as used hereinbefore, defines all possible compoundsmade up of the same atoms bonded by the same sequence of bonds buthaving different three-dimensional structures which are notinterchangeable, which the compounds of the present invention maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of a compound encompasses the mixture of all possiblestereochemically isomeric forms which said compound may possess. Saidmixture may contain all diastereomers and/or enantiomers of the basicmolecular structure of said compound. All stereochemically isomericforms of the compounds of the present invention both in pure form or inadmixture with each other are intended to be embraced within the scopeof the present invention.

[0063] Pure stereoisomeric forms of the compounds and intermediates asmentioned herein are defined as isomers substantially free of otherenantiomeric or diastereomeric forms of the same basic molecularstructure of said compounds or intermediates. In particular, the term‘stereoisomerically pure’ concerns compounds or intermediates having astereoisomeric excess of at least 80% (i. e. minimum 90% of one isomerand maximum 10% of the other possible isomers) up to a stereoisomericexcess of 100% (i.e. 100% of one isomer and none of the other), more inparticular, compounds or intermediates having a stereoisomeric excess of90% up to 100%, even more in particular having a stereoisomeric excessof 94% up to 100% and most in particular having a stereoisomeric excessof 97% up to 100%. The terms ‘enantiomerically pure’ and‘diastereomerically pure’ should be understood in a similar way, butthen having regard to the enantiomeric excess, respectively thediastereomenc excess of the mixture in question.

[0064] Pure stereoisomeric forms of the compounds and intermediates ofthis invention may be obtained by the application of art-knownprocedures. For instance, enantiomers may be separated from each otherby the selective crystallization of their diasteteomeric salts withoptically active acids. Alternatively, enantiomers may be separated bychromatographic techniques using chiral stationary phases. Said purestereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably, if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

[0065] The diastereomeric racemates of formula (I) can be obtainedseparately by conventional methods. Appropriate physical separationmethods which may advantageously be employed are, for example, selectivecrystallization and chromatography, e.g. column chromatography.

[0066] It is clear to a person skilled in the art that the compounds offormula (I) contain at least one asymmetric center and thus may exist asdifferent stereoisomeric forms. This asymmetric center is indicated witha asterisk (*) in the figure below.

[0067] The absolute configuration of each asymmetric center that may bepresent in the compounds of formula (I) may be indicated by thestereochemical descriptors R and S, this R and S notation correspondingto the rules described in Pure Appl. Chem. 1976, 45, 11-30. The carbonatom marked with the asterisk (*) preferably has the R configuration.

[0068] The present invention is also intended to include all isotopes ofatoms occurring on the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example and without limitation, isotopes of hydrogen includetritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0069] Whenever used hereinafter, the term “compounds of formula (I)”,or “the present compounds” or similar term is meant to include thecompounds of general formula (I), their N-oxides, salts, stereoisomericforms, racemic mixtures, prodrugs, esters and metabolites, as well astheir quaternized nitrogen analogues.

[0070] A suitable group of compounds are those compounds according toformula (I) wherein:

[0071] R₉, R_(10a) and R_(10b) are, each independently, hydrogen,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl. C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl orC₁₋₄alkyl optionally substituted with aryl, Het¹, Het², C₃₋₇cycloalkyl,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(O)_(t), hydroxy,cyano, halogen or amino optionally mono- or disubstituted where thesubstituents are selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl; whereby R₉, R_(10a) and the carbon atoms to which theyare attached may also form a C₃₋₇cycloalkyl radical;

[0072] R_(11a) is hydrogen, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl,aryl, aminocarbonyl optionally mono- or disubstituted,aminoC₁₋₄alkylcarbonyloxy optionally mono- or disubstituted,C₁₋₄alkyloxycarbonyl, aryloxycarbonyl, Het¹oxycarbonyl, Het²oxycarbonyl,aryloxycarbonylC₁₋₄alkyl, arylC₁₋₄alkyloxycarbonyl, C₁₋₄alkylcarbonyl,C₃₋₇cycloalkylcarbonyl, C₃₋₇cycloalkyl-C₁₋₄alkyloxycarbonyl,C₃₋₇cycloalkylcarbonyloxy, carboxylC₁₋₄alkylcarbonyloxy,C₁₋₄alkylcarbonyloxy, arylC₁₋₄alkylcarbonyloxy, arylcarbonyloxy,aryloxycarbonyloxy, Het¹carbonyl, Het¹carbonyloxy,Het¹C₁₋₄alkyloxycarbonyl, Het²carbonyloxy, Het²C₁₋₄alkylcarbonyloxy,Het²C₁₋₄alkyloxycarbonyloxy or C₁₋₄alkyl optionally substituted witharyl, aryloxy, Het² or hydroxy; wherein the substituents on the aminogroups are each independently selected from C₁₋₄alkyl, aryl,arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het²,Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl;

[0073] R_(11b) is hydrogen, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,aryl, Het¹, Het² or C₁₋₄alkyl optionally substituted with halogen,hydroxy, C₁₋₄alkylS(═O)_(t), aryl, C₃₋₇cycloalkyl, Het¹, Het², aminooptionally mono- or disubstituted where the substituents are selectedfrom C₁₋₄alkyl, aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl;

[0074] whereby R_(11b) may be linked to the remainder of the moleculevia a sulfonyl group;

[0075] t is zero, 1 or 2;

[0076] L is —C(═O)—, —O—C(═O)—, —NR₈—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—,—NR₈—C₁₋₆alkanediyl-C(═O)—, —S(═O)₂—, —O—S(═O)₂—, —NR₈—S(═O)₂ wherebyeither the C(═O) group or the S(═O)₂ group is attached to the NR₂moiety;

[0077] R₄ is hydrogen, C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, or C₁₋₆alkyl optionally substituted with one or moresubstituents selected from aryl, Het¹, Het², C₃₋₇cycloalkyl,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(═O)_(t), hydroxy,cyano, halogen and amino optionally mono- or disubstituted where thesubstituents are selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl; and

[0078] R₆ is C₁₋₆alkyloxy, Het¹, Het¹oxy, Het², Het²oxy, aryl, aryloxyor amino; and in case -A- is other than C₁₋₆alkanediyl then & may alsobe C₁₋₆alkyl, Het¹C₁₋₄alkyl, Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl,Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl, aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl;whereby each of the amino groups in the definition of R₆ may optionallybe substituted with one or more substituents selected from C₁₋₄alkyl,C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, aryl, arylcarbonyl,aryloxycarbonyl, Het¹, Het², arylC₁₋₄alkyl, Het¹C₁₋₄alkyl orHet²C₁₋₄alkyl.

[0079] A particular group of compounds are those compounds of formula(I) wherein one or more of the following restrictions apply:

[0080] R₁ is hydrogen, Het¹, Het², aryl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,arylC₁₋₆alkyl, more in particular, R₁ is a saturated or partiallyunsaturated monocyclic or bicyclic heterocycle having 5 to 8 ringmembers, which contains one or more heteroatom ring members selectedfrom nitrogen, oxygen or sulfur and which is optionally substituted, orphenyl optionally substituted with one or more substituents;

[0081] R₂ is hydrogen;

[0082] L is —C(═O)—, —O—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—, more inparticular, L is —O—C(═O)— or —O—C₁₋₆alkanediyl-C(═O)—, whereby in eachcase the C(═O) group is attached to the NR₂ moiety;

[0083] R₃ is arylC₁₋₄alkyl, in particular, arylmethyl, more inparticular phenylmethyl;

[0084] R₄ is optionally substituted C₁₋₆alkyl, in particularunsubstituted C₁₋₆alkyl or C₁₋₆alkyl optionally substituted with one ormore substituents selected from aryl, Het¹, Het², C₃₋₇cycloalkyl andamino optionally mono- or disubstituted where the substituents areselected from C₁₋₄alkyl, aryl, Het¹ and Het²;

[0085] A is C₁₋₆alkanediyl, —C(═O)— or C₁₋₆alkanediyl-C(═O)—, inparticular, A is 1,2-ethanediyl, 1,3-propanediyl or —C(═O)—;

[0086] R₅ is hydrogen, C₁₋₆alkyl, Het¹C₁₋₆alkyl, aminoC₁₋₆alkyl wherebythe amino group may optionally be mono- or di-substituted withC₁₋₄alkyl, in particular, R₅ is hydrogen or C₁₋₆alkyl;

[0087] R₆ is C₁₋₆alkyloxy, Het¹, aiyl, amino; and in case -A- is otherthan C₁₋₆alkanediyl then R₆ may also be C₁₋₆alkyl, Het¹C₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl; whereby each of the amino groups mayoptionally be substituted; in particular, R₆ is C₁₋₆alkyloxy, optionallysubstituted amino; and in case -A- is other than C₁₋₆alkanediyl R₆ isC₁₋₆alkyl;

[0088] -A-R₆ is hydroxyC₁₋₆alkyl; or

[0089] R₅ and -A-R₆ taken together with the nitrogen atom to which theyare attached may also form Het¹.

[0090] A special group of compounds are those compounds of formula (I)wherein R₁ is Het¹, aryl, Het²C₁₋₆alkyl; R₂ is hydrogen; L is —C(═O)—,—O—C(═O)—, —O—CH₂—C(═O)—, whereby in each case the C(═O) group isattached to the NR₂ moiety; R₃ is phenyl-methyl; and R₄ is C₁₋₆alkyl.

[0091] Also a special group of compounds are those compounds of formula(I) wherein A is C₁₋₆alkanediyl or —C(═O)—; R₅ is hydrogen or methyl; R₆is C₁₋₆alkyloxy, Het¹, amino; and in case -A- is other thanC₁₋₆alkanediyl then R₆ may also be C₁₋₆alkyl, Het¹C₁₋₄alkyl oraminoC₁₋₄alkyl; whereby each of the amino groups may optionally besubstituted.

[0092] A suitable group of compounds are those compounds of formula (I)wherein A is C₁₋₆alkanediyl or —C(═O)—; R₅ is hydrogen or methyl; R₆ isHet²; and in case -A- is other than C₁₋₆alkanediyl then R₆ may also beHet²C₁₋₄alkyl; whereby each of the amino groups may be optionallysubstituted.

[0093] Yet another special group of compounds are those compounds offormula (I) wherein A is —C(═O)-and R₆ is C₁₋₆alkyloxy or C₁₋₆alkyl.

[0094] Another group of compounds are those compounds of formula (I)wherein wherein A is —C(═O)— and & is Het², Het¹ or optionally mono- ordisubstituted aminoC₁₋₆alkyl.

[0095] An interesting group of compounds are those compounds of formula(I) wherein -A- is carbonyl and R₆ is aryl, Het¹C₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl, whereby the amino groups mayoptionally be substituted; or -A- is carbonyl, R₆ is C₁₋₄alkyl and R₅ isHet¹C₁₋₆alkyl or aminoC₁₋₆alkyl whereby the amino group may optionallybe mono- or di-substituted with C₁₋₄alkyl.

[0096] Another interesting group of compounds are those compounds offormula (I) wherein -A- is C₁₋₆alkanediyl and R₆ is amino and Het¹;whereby the amino group may optionally be mono- or di-substituted withC₁₋₄alkyl.

[0097] Another interesting group of compounds are those compounds offormula (I) wherein R₁ hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, arylC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl, aryl, Het¹, Het¹C₁₋₆alkyl,Het², Het²C₁₋₆alkyl; wherein Het¹ in the definition of R₁ is a saturatedor partially unsaturated monocyclic/heterocycle having 5 or 6 ringmembers, which contains one or more heteroatom ring members selectedfrom nitrogen, oxygen or sulfur and which is optionally substituted onone or more carbon atoms.

[0098] Another interesting group of compounds are those compounds offormula (I) wherein L is —O—C₁₋₆alkanediyl-C(═O)—.

[0099] Another interesting group of compounds are those compounds offormula (I) wherein

[0100] A is C₁₋₆alkanediyl, —C(═O)— or C₁₋₆alkanediyl-C(═O)—; wherebythe point of attachment to the nitrogen atom is the C₁₋₆alkanediyl groupin those moieties containing said group;

[0101] R₅ is hydrogen, C₁₋₆alkyl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,aminoC₁₋₆alkyl whereby the amino group may optionally be mono- ordi-substituted with C₁₋₄alkyl; and

[0102] in case -A- is —C(═O)-then R⁶ is C₁₋₆alkyloxy, Het¹, Het¹oxy orHet²oxy, aryl, Het¹C₁₋₄alkyl, Het¹ oxyC₁₋₄alkyl, Het²C₁₋₄alkyl,Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl, aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl; and

[0103] in case -A- is C₁₋₆alkanediyl then R₆ is amino, C₁₋₆alkyloxy,Het¹, Het¹oxy- or Het²oxy; and

[0104] in case -A- is C₁₋₆alkanediyl-C(═O)-then R₆ is C₁₋₆alkyloxy,Het¹, Het¹oxy or Het²oxy, aryl, C₁₋₆alkyl, Het¹C₁₋₄alkyl,Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl, Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl;

[0105] whereby each of the amino groups in the definition of R₆ mayoptionally be substituted with one or more substituents selected fromC₁₋₄alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, aryl, arylcarbonyl,aryloxycarbonyl, Het¹, Het², aryl-C₁₋₄alkyl, Het¹C₁₋₄alkyl orHet²C₁₋₄alkyl; and

[0106] R₅ and -A-R₆ taken together with the nitrogen atom to which theyare attached may also form Het¹ whereby Het¹ is substituted by at leastan oxo group.

[0107] A particular group of compounds are those compounds of formula(I) wherein one or more of the following restrictions apply:

[0108] R₁ is hydrogen, Het¹, Het², aryl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,arylC₁₋₆alkyl, more in particular, R₁ is a saturated or partiallyunsaturated monocyclic or bicyclic heterocycle having 5 to 8 ringmembers, which contains one or more heteroatom ring members eachindependently selected from nitrogen, oxygen or sulfur and which isoptionally substituted, or phenyl optionally substituted with one ormore substituents;

[0109] R₂ is hydrogen;

[0110] L is —C(═O)—, —O—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—, more inparticular, L is —O—C(═O)— or —O—C₁₋₆alkanediyl-C(═O)—, whereby in eachcase the C(═O) group is attached to the NR₂ moiety;

[0111] R₃ is arylC₁₋₄alkyl, in particular, arylmethyl, more inparticular phenylmethyl;

[0112] R₄ is optionally substituted C₁₋₆alkyl, in particularunsubstituted C₁₋₆alkyl or C₁₋₆alkyl optionally substituted with one ormore substituents each independently selected from aryl, Het¹, Het²,C₃₋₇cycloalkyl and amino optionally mono- or disubstituted where thesubstituents are each independently selected from C₁₋₄alkyl, aryl, Het¹and Het²;

[0113] A is C₁₋₆alkanediyl, —C(═O)— or C₁₋₆alkanediyl-C(═O)—, inparticular, A is 1,2-ethanediyl, 1,3-propanediyl or —C(═O)—;

[0114] R₅ is hydrogen, C₁₋₆alkyl, Het¹C₁₋₆alkyl, aminoC₁₋₆alkyl wherebythe amino group may optionally be mono- or di-substituted withC₁₋₄alkyl, in particular, R₅ is hydrogen or C₁₋₆alkyl;

[0115] R₆ is C₁₋₆alkyloxy, Het¹, aryl, amino; and in case -A- is otherthan C₁₋₆alkaflediyl then R₆ may also be C₁₋₆alkyl, Het¹C₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₆alkyl; whereby each of the amino groups mayoptionally be substituted; in particular, RX is C₁₋₆alkyloxy, optionallysubstituted amino; and in case -A- is other than C₁₋₆alkanediyl R₆ isC₁₋₆alkyl;

[0116] -A-R₆ is hydroxyC₁₋₆alkyl; or

[0117] R₅ and -A-R₆ taken together with the nitrogen atom to which theyare attached may also form Het¹.

[0118] Another interesting group of compounds are those compounds offormula (I) wherein -A- is C₁₋₆alkanediyl and R₆ is amino or Het¹;whereby the amino group may optionally be mono- or di-substituted withC₁₋₄alkyl.

[0119] Another interesting group of compounds are those compounds offormula (I) wherein

[0120] A is C₁₋₆alkanediyl, —C(═O)— or C₁₋₆alkanediyl-C(═O)—; wherebythe point of attachment to the nitrogen atom is the C₁₋₆alkanediyl groupin those moieties containing said group;

[0121] R₅ is hydrogen, C₁₋₆alkyl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,aminoC₁₋₆alkyl whereby the amino group may optionally be mono- ordi-substituted with C₁₋₄alkyl; and

[0122] in case -A- is —C(═O)-then R₆ is C₁₋₆alkyloxy, Het¹, Het¹oxy orHet²oxy, aryl, Het¹C₁₋₄alkyl, Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl,Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl, aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl; and

[0123] in case -A- is C₁₋₆alkanediyl then R₆ is amino, C₁₋₆alkyloxy,Het¹, Het¹oxy or Het²oxy; and

[0124] in case -A- is C₁₋₆alkanediyl-C(═O)-then R₆ is C₁₋₆alkyloxy,Het¹, Het¹oxy or, Het²oxy, aryl, C₁₋₆alkyl, Het¹C₁₋₄alkyl,Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl, Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl;

[0125] whereby each of the amino groups in the definition of R₆ mayoptionally be substituted with one or more substituents eachindependently selected from C₁₋₄alkyl, C₁₋₄alkylcarbonyl,C₁₋₄alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het¹, Het²,arylC₁₋₄alkyl, Het¹C₁₋₄alkyl or Het²C₄alkyl; and

[0126] R₅ and -A-R₆ taken together with the nitrogen atom to which theyare attached may also form Het¹ whereby Het¹ is substituted by at leastan oxo group.

[0127] Another group of compounds are those of formula (I) wherein R₁ isHet²C₁₋₆alkyl, L is —C(═O)—, —O—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—; inparticular the Het² moiety in the definition of R₁ is an aromaticheterocycle having 5 or 6 ring members, which contain one or moreheteroatom ring members each independently selected from nitrogen,oxygen or sulfur, more in particular the Het² moiety is an aromaticheterocycle having or 6 ring members, which contain two or moreheteroatom ring members each independently selected from nitrogen,oxygen or sulfur.

[0128] Suitably, the SO₂ moiety of the sulfonamide in the compounds ofthe present invention is para vis-a-vis the nitrogen of the benzoxazolemoiety.

[0129] Another group of suitable compounds are those of formula (I)wherein A is C₁₋₆alkanediyl or —C(═O)—; R₅ is hydrogen or methyl; and R₆is C₁₋₆alkyloxy, Het¹, Het², amino or amino C₁₋₆alkyl; whereby eachamino optionally may be mono- or disubstituted where the substituentsare each independently selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl.

[0130] Another group of suitable compounds are those of formula (I)wherein R₁ is Het² or Het²C₁₋₆alkyl; wherein said Het² in the definitionof R₁ is an aromatic heterocycle having at least one heteroatom eachindependently selected from nitrogen, oxygen and sulfur; L is —C(═O)—,—O—C(═O)— or —O—C₁₋₆alkyl-C(═O)—; A is C₁₋₆alkanediyl or —C(═O)—; R₅ ishydrogen or methyl; and R₆ is C₁₋₆alkyloxy, Het¹, Het², amino oraminoC₁₋₆alkyl; whereby each amino optionally may be mono- ordisubstituted, where the substituents are each independently selectedfrom C₁₋₄alkyl, aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl.

[0131] Another group of suitable compounds are those of formula (I)wherein R₁ is 2-thiazolylmethyl-; and L is —O—C(═O)—.

[0132] Another group of suitable compounds are those of formula (I)wherein R₁ is hydrogen; A is —C(═O)—; and R₆ is Het²; wherein said Het²contains 5 or 6 ring members and one heteroatom selected from nitrogen,oxygen or sulfur.

[0133] Another group of compounds are those of formula (I) wherein R₁ isHet¹, having 8 ring members and two heteroatoms each independentlyselected from nitrogen, oxygen or sulfur; L is —O—C(═O)—; R₅ is hydrogenor methyl; A is —C(═O)—, C₁₋₆alkanediyl; and R₆ is optionally mono- ordisubstituted aminoC₁₋₄alkyl, Het¹ or Het²; wherein said Het² contains 5or 6 ring members and one heteratom selected from nitrogen, oxygen orsulfur; wherein the amino substituents are each independently selectedfrom C₁₋₄alkyl, aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl.

[0134] The compounds of formula (I) can generally be prepared usingprocedures analogous to those procedures described in WO 95/06030, WO96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO97/18205.

[0135] Particular reaction procedures to make the present compounds aredescribed below. In the preparations described below, the reactionproducts maybe isolated from the medium and, if necessary, furtherpurified according to methodologies generally known in the art such as,for example, extraction, crystallization, trituration andchromatography.

[0136] The 2-acetamido-6-chlorosulfonylbenzoxazole (intermediate a-2)was prepared following the procedure described in EP-A-0,445,926.

[0137] Intermediates a-4 were prepared by reacting an intermediate a-3,prepared according to the procedure described in WO97/18205 and alsodepicted in scheme C, with an intermediate a-2 in a reaction-inertsolvent such as dichloromethane, and in the presence of a base such astriethylamine and at low temperature, for example at 0° C. The Boc groupin the intermediate a-3 is a protective teri-butyloxycarbonyl group. Itmay conveniently be replaced by another suitable protective group suchas phtalimido or benzyloxycarbonyl. Using intermediate a-4 as a startingmaterial, intermediate a-5 was deprotected using an acid such astrifluoroacetic acid in a suitable solvent such as dichloromethane. Theresulting intermediate may be further reacted with an intermediate offormula R₁-L-(leaving group) in the presence of a base such astriethylamine and optionally in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloric acid (EDC) oran alcohol such as tert-butanol, and in a suitable solvent such asdichloromethane; thus forming intermediates a-6. Particularly,intermediates of formula R₁—C(═O)—OH are suitable to further react withan intermediate a-5.

[0138] Alternatively, intermediates a-4 may be deprotected with a strongacid such as hydrochloric acid in isopropanol, in a suitable solventsuch as a mixture of ethanol and dioxane, thus preparing an intermediatea-7. Intermediates a-8 can be prepared analogqusly to the proceduredescribed for the preparation of intermediates a-6.

[0139] The procedure described in scheme A may also be used to prepareintermediates of formula a-6 wherein benzoxazole is substituted with acarbamate instead of an amide.

[0140] Intermediate b-4 can be prepared according to the proceduredescribed in scheme A. Intermediate b-5 can be prepared by for instancerefluxing the 2(3H)-benzoxazolone derivative b-4 in the presence of abase such as, for example, sodiumhydroxide. Said intermediate b-5 canthen be cyclized again using a reagent such as alkyl xanthic acidpotassium salt (alkyl dithiocarbonate potassium salt) in a suitablesolvent such as, for example, ethanol at reflux temperature, thuspreparing a 243H)-benzoxazolethione of formula b-6. Intermediate b-6 maythen be derivatized with an amine of formula H₂N-A-R₆ in a suitablesolvent such as acetonitrile to obtain an intermediate b-7.

[0141] Debenzylation may be performed using art-known techniques such asthe use of Pd on carbon in the presence of H₂ in a suitable solvent. Thethus formed intermediate of formula b-8 may then be reacted with anintermediate of formula R₁-L-(leaving group) in the presence of a basesuch as triethylamine and optionally in the presence of EDC or analcohol such as tert-butanol, and in a suitable solvent such asdichloromethane, thus obtaining an intermediate b-9.

[0142] A particular way of preparing acetamide substituted benzoxazolesis depicted in scheme C.

[0143] Intermediate c-1, prepared following the procedure as describedin Scheme A, may be reacted with chloroacetylchloride, or a functionalanalogue, in the presence of a base such as triethylamine and in asolvent such as 1,4-dioxane in order to obtain an amide of formula c-2.Said intermediate c-2 can further be reacted with an amine of formulaNR_(a)R_(b) whereby R_(a) and R_(b) are defined as the possiblesubstituents on an amino group in the variable R₆.

[0144] Another particular way of preparing acetamide substitutedbenzoxazoles is depicted in scheme D.

[0145] Intermediate d-2 can be prepared by treating intermediate d-1,prepared following the procedure described in scheme A, with a base suchas sodiumcarbonate in an aqueous medium such as a water dioxane mixture.The synthesis steps depicted in scheme D to obtain intermediate d-6 areall analogous to reaction procedures described in the above synthesisschemes.

[0146] A number of intermediates and starting materials used in theforegoing preparations are known compounds, while others may be preparedaccording to art-known methodologies of preparing said or similarcompounds.

[0147] Intermediate e-2, corresponding to intermediate a-3 in scheme A,may be prepared by adding an amine of formula H₂N—R₄ to an intermediatee-1 in a suitable solvent such as isopropanol.

[0148] A mixture of the 2-aminobenzoxazole f-1 in dichloromethane wasstirred under an inert atmosphere such as nitrogen. R₆—COOH, EDC andHOBT (1-hydroxy-1-H-benzotriazole) were added. The mixture was stirredat room temperature for 48 h. Water was added, the water layer wasextracted with dichloromethane and the combined organic layers werewashed with brine, dried under MgSO₄ and the solvent was evaporatedunder reduced pressure. Purification was performed on silica yieldingf-2.

[0149] The compounds of formula (I) may also be converted to thecorresponding N-oxide forms following art-known procedures forconverting a trivalent nitrogen into its N-oxide form. Said N-oxidationreaction may generally be carried out by reacting the starting materialof formula (I) with an appropriate organic or inorganic peroxide.Appropriate inorganic peroxides comprise, for example, hydrogenperoxide, alkali metal or earth alkaline metal peroxides, e.g. sodiumperoxide, potassium peroxide; appropriate organic peroxides may compriseperoxy acids such as, for example, benzenecarboperoxoic acid or halosubstituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoicacid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides,e.g. tert-butyl hydroperoxide. Suitable solvents are, for example,water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g.toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

[0150] An interesting group of intermediates are those intermediates offormula a-8, b-8 or c-1 wherein -A-R₆ is hydrogen. Said intermediatesmay also have pharmacological properties similar to thosepharmacological properties of the compounds of formula (I).

[0151] The present compounds can thus be used in animals, preferably inmammals, and in particular in humans as pharmaceuticals per se, inmixtures with one another or in the form of pharmaceutical preparations.

[0152] Furthermore, the present invention relates to pharmaceuticalpreparations which as active constituents contain an effective dose ofat least one of the compounds of formula (I) in addition to customarypharmaceutically innocuous excipients and auxiliaries. Thepharmaceutical preparations normally contain 0.1 to 90% by weight of acompound of formula (I). The pharmaceutical preparations can be preparedin a manner known per se to one of skill in the art. For this purpose,at least one of a compound of formula (I), together with one or moresolid or liquid pharmaceutical excipients and/or auxiliaries and, ifdesired, in combination with other pharmaceutical active compounds, arebrought into a suitable administration form or dosage form which canthen be used as a pharmaceutical, in human medicine or veterinarymedicine.

[0153] Pharmaceuticals which contain a compound according to theinvention can be administered orally, parenterally, e.g., intravenously,rectally, by inhalation, or topically, the preferred administrationbeing dependent on the individual case, e.g., the particular course ofthe disorder to be treated. Oral administration is preferred.

[0154] The person skilled in the art is familiar on the basis of hisexpert knowledge with the auxiliaries which are suitable for the desiredpharmaceutical formulation. Beside solvents, gel-forming agents,suppository bases, tablet auxiliaries and other active compoundcarriers, antioxidants, dispersants, emulsifiers, antifoams, flavorcorrigents, preservatives, solubilizers, agents for achieving a depoteffect, buffer substances or colorants are also useful.

[0155] Due to their favorable pharmacological properties, particularlytheir activity against multi-drug resistant HIV protease enzymes, thecompounds of the present invention are useful in the treatment ofindividuals infected by HIV and for the prophylaxis of theseindividuals. In general, the compounds of the present invention may beuseful in the treatment of warm-blooded animals infected with viruseswhose existence is mediated by, or depends upon, the protease enzyme.Conditions which may be prevented or treated with the compounds of thepresent invention, especially conditions associated with HIV and otherpathogenic retroviruses, include AIDS, AIDS-related complex (ARC),progressive generalized lymphadenopathy (PGL), as well as chronic CNSdiseases caused by retroviruses, such as, for example HIV mediateddementia and multiple sclerosis.

[0156] The compounds of the present invention or any subgroup thereofmay therefore be used as medicines against above-mentioned conditions.Said use as a medicine or method of treatment comprises the systemicadministration to HIV-infected subjects of an amount effective to combatthe conditions associated with HIV and other pathogenic retroviruses,especially HIV-1. Consequently, the compounds of the present inventioncan be used in the manufacture of a medicament useful for treatingconditions associated with HIV and other pathogenic retroviruses, inparticular medicaments useful for treating patients infected withmulti-drug resistant HIV virus.

[0157] In a preferred embodiment, the invention relates to the use of acompound of formula (I) or any subgroup thereof in the manufacture of amedicament for treating or combating infection or disease associatedwith multi-drug resistant retrovirus infection in a mammal, inparticular HIV-1 infection. Thus, the invention also relates to a methodof treating a retroviral infection, or a disease associated withmulti-drug resistant retrovirus infection comprising administering to amammal in need thereof an effective amount of a compound of formula (I)or a subgroup thereof

[0158] In another preferred embodiment, the present invention relates tothe use of formula (I) or any subgroup thereof in the manufacture of amedicament for inhibiting a protease of a multi-drug resistantretrovirus in a mammal infected with said retrovirus, in particularHIV-1 retrovirus.

[0159] In another preferred embodiment, the present invention relates tothe use of formula (I) or any subgroup thereof in the manufacture of amedicament for inhibiting multi-drug resistant retroviral replication,in particular HIV-1 replication.

[0160] The compounds of the present invention may also find use ininhibiting ex vivo samples containing HIV or expected to be exposed toHIV. Hence, the present compounds may be used to inhibit HIV present ina body fluid sample which contains or is suspected to contain or beexposed to HIV.

[0161] Also, the combination of an antiretroviral compound and acompound of the present invention can be used as a medicine. Thus, thepresent invention also relates to a product containing (a) a compound ofthe present invention, and (b) another antiretroviral compound, as acombined preparation for simultaneous, separate or sequential use intreatment of retroviral infections, in particular, in the treatment ofinfections with multi-drug resistant retroviruses. Thus, to combat ortreat HIV infections, or the infection and disease associated with HIVinfections, such as Acquired Immunodeficiency Syndrome (AIDS) or AIDSRelated Complex (ARC), the compounds of this invention may beco-administered in combination with for instance, binding inhibitors,such as, for example, dextran sulfate, suramine, polyanions, solubleCD4; fusion inhibitors, such as, for example, T20. T1249, SHC-C;co-receptor binding inhibitors, such as, for example, AMD 3100(Bicyclams), TAK 779; RT inhibitors, such as, for example, foscarnet andprodrugs; nucleoside RTIs, such as, for example, AZT, 3TC, DDC, DDI,D4T, Abacavir, FTC, DAPD, dOTC; nucleotide RTls, such as, for example,PMEA, PMPA (tenofovir); NNRTIs, such as, for example, nevirapine,delavirdine, efavirenz, 8 and 9-Cl TIBO (tivirapine), loviride, TMC-125,TMC-120, IMKC-442, UC 781, UC 782, Capravirine, DPC 961, DPC₉₆₃, DPCO82,DPCO83, calanolide A, SJ-3366, TSAO, 4″-deaminated TSAO; RNAse Hinhibitors, such as, for example, SP1093V, PD126338; TAT inhibitors,such as, for example, RO-5-3335, K12, K37; integrase inhibitors, suchas, for example, L 708906, L 731988; protease inhibitors, such as, forexample, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir,lopinavir, palinavir, BMS 186316, BMS 232632, DPC 681, DPC 684,tipranavir, AG1776, DMP 450, GS3333, KNI-413, KNI-272, L754394, L756425,LG-71350, PD161374, PD173606, PD177298, PD178390, PD178392, PNU 140135,maslinic acid, U-140690; glycosylation inhibitors, such as, for example,castanospermine, deoxynojirimycine.

[0162] The combination may in some cases provide a synergistic effect,whereby viral infectivity and its associated symptoms may be prevented,substantially reduced, or eliminated completely.

[0163] The compounds of the present invention may also be administeredin combination with immunomodulators (e.g., bropirimine, anti-humanalpha interferon antibody, IL-2, methionine enkephalin, interferonalpha, and naltrexone) with antibiotics (e.g., pentamidine isothiorate)cytokines (e.g. Th2), modulators of cytokines, chemokines (e.g. CCR5) orhormones (e.g. growth hormone) to ameliorate, combat, or eliminate HIVinfection and its symptoms.

[0164] The compounds of the present invention may also be administeredin combination with modulators of the metabolization followingapplication of the drug to an individual. These modulators includecompounds that interfere with the metabolization at cytochromes, such ascytochrome P450. It is known that several isoenzymes exist of cytochromeP450, one of which is cytochrome P450 3A4. Ritonavir is an example of amodulator of metabolization via cytochrome P450.

[0165] For an oral administration form, compounds of the presentinvention are mixed with suitable additives, such as excipients,stabilizers or inert diluents, and brought by means of the customarymethods into the suitable administration forms, such as tablets, coatedtablets, hard capsules, aqueous, alcoholic, or oily solutions. Examplesof suitable inert carriers are gum arabic, magnesia, magnesiumcarbonate, potassium phosphate, lactose, glucose, or starch, inparticular, corn starch. In this case the preparation can be carried outboth as dry and as moist granules. Suitable oily excipients or solventsare vegetable or animal oils, such as sunflower oil or cod liver oil.Suitable solvents for aqueous or alcoholic solutions are water, ethanol,sugar solutions, or mixtures thereof. Polyethylene glycols andpolypropylene glycols are also useful as further auxiliaries for otheradministration forms.

[0166] For subcutaneous or intravenous administration, the activecompounds, if desired with the substances customary therefor such assolubilizers, emulsifiers or further auxiliaries, are brought intosolution, suspension, or emulsion. The compounds of formula (I) can alsobe lyophilized and the lyophilizates obtained used, for example, for theproduction of injection or infusion preparations. Suitable solvents are,for example, water, physiological saline solution or alcohols, e.g.ethanol, propanol, glycerol, in addition also sugar solutions such asglucose or mannitol solutions, or alternatively mixtures of the varioussolvents mentioned.

[0167] Suitable pharmaceutical formulations for administration in theform of aerosols or sprays are, for example, solutions, suspensions oremulsions of the compounds of formula (I) or their physiologicallytolerable salts in a pharmaceutically acceptable solvent, such asethanol or water, or a mixture of such solvents. If required, theformulation can also additionally contain other pharmaceuticalauxiliaries such as surfactants, emulsifiers and stabilizers as well asa propellant. Such a preparation customarily contains the activecompound in a concentration from approximately 0.1 to 50%, in particularfrom approximately 0.3 to 3% by weight.

[0168] In order to enhance the solubility and/or the stability of thecompounds of formula (I) in pharmaceutical compositions, it can beadvantageous to employ α-, β- or γ-cyclodextrins or their derivatives.Also co-solvents such as alcohols may improve the solubility and/or thestability of the compounds of formula (I) in pharmaceuticalcompositions. In the preparation of aqueous compositions, addition saltsof the subject compounds are obviously more suitable due to theirincreased water solubility.

[0169] Appropriate cyclodextrins are α-, β- or γ-cyclodextrins (CDs) orethers and mixed ethers thereof wherein one or more of the hydroxygroups of the anhydroglucose units of the cyclodextrin are substitutedwith C₁₋₆alkyl, particularly methyl, ethyl or isopropyl, e.g. randomlymethylated β-CD; hydroxyC₁₋₆alkyl, particularly hydroxyethyl,hydroxypropyl or hydroxybutyl; carboxyC₁₋₆alkyl, particularlycarboxymethyl or carboxyethyl; C₁₋₆alkyl-carbonyl, particularly acetyl;C₁₋₆alkyloxycarbortylC₁₋₆alkyl or carboxyC₁₋₆alkyloxyC₁₋₆alkyl,particularly carboxymethoxypropyl or carboxyethoxypropyl;C₁₋₆alkylcarbonyloxyC₁₋₆alkyl, particularly 2-acetyloxypropyl.Especially-noteworthy as complexants and/or solubilizers are β-CD,randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β—CD).

[0170] The term mixed ether denotes cyclodextrin derivatives wherein atleast two cyclodextrin hydroxy groups are etherified with differentgroups such as, for example, hydroxy-propyl and hydroxyethyl.

[0171] An interesting way of formulating the present compounds incombination with a cyclodextrin or a derivative thereof has beendescribed in EP-A-721,331. Although the formulations described thereinare with antifungal active ingredients, they are equally interesting forformulating the compounds of the present invention. The formulationsdescribed therein are particularly suitable for oral administration andcomprise an antifungal as active ingredient, a sufficient amount of acyclodextrin or a derivative thereof as a solubilizer, an aqueous acidicmedium as bulk liquid carrier and an alcoholic co-solvent that greatlysimplifies the preparation of the composition. Said formulations mayalso be rendered more palatable by adding pharmaceutically acceptablesweeteners and/or flavors.

[0172] Other convenient ways to enhance the solubility of the compoundsof the present invention in pharmaceutical compositions are described inWO 94/05263, WO 98/42318, EP-A-499,299 and WO 97/44014, all incorporatedherein by reference.

[0173] More in particular, the present compounds may be formulated in apharmaceutical composition comprising a therapeutically effective amountof particles consisting of a solid dispersion comprising (a) a compoundof formula (I), and (b) one or more pharmaceutically acceptablewater-soluble polymers.

[0174] The term “a solid dispersion” defines a system in a solid state(as opposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components. When said dispersion ofthe components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermo-dynamics, such a solid dispersion is referred to as “a solidsolution”. Solid solutions are preferred physical systems because thecomponents therein are usually readily bioavailable to the organisms towhich they are administered.

[0175] The term “a solid dispersion” also comprises dispersions whichare less homogenous throughout than solid solutions. Such dispersionsare not chemically and physically uniform throughout or comprise morethan one phase.

[0176] The water-soluble polymer in the particles is conveniently apolymer that has an apparent viscosity of 1 to 100 mPa.s when dissolvedin a 2% aqueous solution at 20° C. solution.

[0177] Preferred water-soluble polymers are hydroxypropylmethylcelluloses or HPMC. HPMC having a methoxy degree of substitutionfrom about 0.8 to about 2.5 and a hydroxypropyl molar substitution fromabout 0.05 to about 3.0 are generally water soluble. Methoxy degree ofsubstitution refers to the average number of methyl ether groups presentper anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molarsubstitution refers to the average number of moles of propylene oxidewhich have reacted with each anhydroglucose unit of the cellulosemolecule.

[0178] The particles as defined hereinabove can be prepared by firstpreparing a solid dispersion of the components, and then optionallygrinding or milling that dispersion. Various techniques exist forpreparing solid dispersions including melt-extrusion, spray-drying andsolution-evaporation, melt-extrusion being preferred.

[0179] It may further be convenient to formulate the present compoundsin the form of nanoparticles which have a surface modifier adsorbed onthe surface thereof in an amount sufficient to maintain an effectiveaverage particle size of less than 1000 nm. Useful surface modifiers arebelieved to include those which physically adhere to the surface of theantiretroviral agent but do not chemically bond to the antiretroviralagent.

[0180] Suitable surface modifiers can preferably be selected from knownorganic and inorganic pharmaceutical excipients. Such excipients includevarious polymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

[0181] Yet another interesting way of formulating the present compoundsinvolves a pharmaceutical composition whereby the present compounds areincorporated in hydrophilic polymers and applying this mixture as a coatfilm over many small beads, thus yielding a composition with goodbioavailability which can conveniently be manufactured and which issuitable for preparing pharmaceutical dosage forms for oraladministration.

[0182] Said beads comprise (a) a central, rounded or spherical core, (b)a coating film of a hydrophilic polymer and an antiretroviral agent and(c) a seal-coating polymer layer.

[0183] Materials suitable for use as cores in the beads are manifold,provided that said materials are pharmaceutically acceptable and haveappropriate dimensions and firmness. Examples of such materials arepolymers, inorganic substances, organic substances, and saccharides andderivatives thereof.

[0184] Another aspect of the present invention concerns a kit orcontainer comprising a compound of formula (I) in an amount effectivefor use as a standard or reagent in a test or assay for determining theability of a potential pharmaceutical to inhibit HIV protease, HIVgrowth, or both. This aspect of the invention may find its use inpharmaceutical research programs.

[0185] The compounds of the present invention can be used in phenotypicresistance monitoring assays, such as known recombinant assays, in theclinical management of resistance developing diseases such as HIV. Aparticularly useful resistance monitoring system is a recombinant assayknown as the Antivirogram™. The Antivirogram™ is a highly automated,high throughput, second generation, recombinant assay that can measuresusceptibility, especially viral susceptibility, to the compounds of thepresent invention. (Hertogs K, de Bethune M P, Miller V et al.Antimicrob Agents Chernother, 1998; 42(2):269-276, incorporated byreference).

[0186] The compounds of the present invention may also be linked tomaleimide or derivatives thereof to form conjugates.

[0187] The dose of the present compounds or of the physiologicallytolerable salt(s) thereof to be administered depends on the individualcase and, as customary, is to be adapted to the conditions of theindividual case for an optimum effect. Thus it depends, of course, onthe frequency of administration and on the potency and duration ofaction of the compounds employed in each case for therapy orprophylaxis, but also on the nature and severity of the infection andsymptoms, and on the sex, age, weight and individual responsiveness ofthe human or animal to be treated and on whether the therapy is acute orprophylactic. Customarily, the daily dose of a compound of formula (I)in the case of administration to a patient approximately 75 kg in weightis 1 mg to 3 g, suitably 1 mg to 1 g, preferably 3 mg to 0.5 g, morepreferably 5 mg to 300 mg. The dose can be administered in the form ofan individual dose, or divided into several, e.g. two, three, or four,individual doses.

EXPERIMENTAL PART Preparation of the Compounds of Formula (I) and TheirIntermediates EXAMPLE 1

[0188] Preparation of Compound 1

[0189] a) A mixture of 5 g 2-acetamidobenzoxazole and 20 mlchlorosulfonic acid in dichloromethane was heated to 60° C. for 2 hours(h). After cooling the mixture was poured into ice. The organic layerwas separated and dried over MgSO₄, thus yielding2-acetamido-6-chlorosulfonylbenzoxazole (interm. 1)

[0190] b) A mixture of 3.4 g of[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-(phenylmethyl)propyl]carbamicacid 1,1-dimethylethyl ester, prepared analogously to the proceduredescribed in WO 97/18205, and 2.6 g of triethylamine in 100 ml ofdichloromethane was stirred at 0° C. Then 2.8 g of2-acetamido-6-chlorosulfonylbenzoxazole was added and the reactionmixture stirred overnight at room temperature. After washing with water,the organic layer was separated, dried and evaporated. The brown solidobtained was reslurried in warm dilsopropyl ether, cooled and filteredoff, thus yielding 88% (5.1 g) of intern. 2:

[0191] c) To a mixture of 1.2 g of intermediate 2 in 25 ml ofdichloromethane, 2.3 ml of trifluoracetic acid were added. The reactionmixture as stirred at room temperature for 6 hours. Extradichloromethane was added and washed with NaHCO₃ solution. The organiclayer was dried and evaporated under reduced pressure, yielding 970 mg(99%) of intermediate 3:

[0192] d) To a mixture of 1.1 g intermediate 3 and 364 mg triethylaminein dichloromethane was added 685 mg1-[[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]-oxy]-2,5-pyrrolidinedione(described in WO9967417). This mixture is stirred at room temperaturefor 12 hours. After evaporation of dichloromethane under reducedpressure, the crude product is purified on silica. Thus, 900 mg ofcompound 1 was obtained with a yield of 59%.

EXAMPLE 2

[0193] Preparation of Compound 59

[0194] a) A mixture of 1 g of[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)amino]-1-(phenylmethyl)propyl]carbamicacid 1,1-dimethylethyl ester and 901 mg of triethylarnine in 9 ml ofdichloromethane was stirred at 0° C. Then 1 g of2-(Ethoxycarbamoyl)-6-chlorosulfonylbenzoxazole was added and thereaction mixture stirred overnight at room temperature. After washingwith sat NaHCO₃, the organic layer was separated, dried and evaporated,yielding 1.7 g (94%) of intermediate 4

[0195] b) To a mixture of 1.7 g of intermediate 4 in 25 ml ofdichloromethane, 3.2 g of trifluoracetic acid were added. The reactionmixture as stirred at room temperature for 6 hours. Extradichloromethane was added and washed with NaHCO₃ solution. The organiclayer was dried and evaporated under reduced pressure yielding 1.4 g(99%) of intermediate 5

[0196] c) A mixture of 380 mg of intermediate 5, 107 mg of1-hydroxybenzotriazole, 154 mg of1-(3-dimethylaminopropyl)-3-ethylcarbodiumide hydrochloric acid and 143mg of 2-(2,6-dimethylphenoxy)acetic acid in 20 ml of dichloromethane,was stirred overnight at room temperature. The reaction mixture was thenwashed with 5% HCl, saturated NaHCO₃ solution and brine. The organiclayer was separated, dried and evaporated. The residue was purified bypreparative-HPLC, yielding 141 mg (28%) of compound 5.

EXAMPLE 3

[0197] Preparation of Compound 3

[0198] To a mixture of 1.2 g intermediate 5 and 364 mg triethylamine indichloromethane was added 685 mg1-[[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidinedione(described in W09967417). This mixture is stirred at room temperaturefor 12 hours. After evaporation of dichloromethane under reducedpressure, the crude product is purified on silica, thus yielding 1.1 g(70%) of compound 3.

EXAMPLE 4

[0199] Preparation of Compound 2

[0200] a) To a mixture of 8 gβ-[bis(phenylmethyl)amino]-α-[[(2-methylpropyl)amino)methyl]-(αR,βS)-benzenepropanol,prepared following the procedure in WO95/14653, and 3.2 g triethylaminein 150 ml dichloromethane was added at 0° C. 3.9 g6-chlorosulfonyl-benzoxazolone (prepared as described in EP 0403947).After stirring for 24 hours at room temperature the reaction mixture waswashed with sat. NaHCO₃, 8 g of intermediate 6:

[0201] b) A mixture of 5.2 g intermediate 6 in 60 ml 10% NaOH-solutionwas heated to reflux overnight. After cooling the reaction mixture wasacidified to pH=8 with 15% HCl. The aqueous phase was extracted twotimes with ethylacetate, yielding 3 g of intermediate 7:

[0202] c) To a solution of 1.5 g intermediate 7 in ethanol was added 361mg ethylpotassium xanthate. After refluxing this mixture for 16 hours,ethanol was removed under vacuum. To the residue was added H₂O. Afteracidification to pH=6 the precipitate was filtered of, yielding, afterdrying, 1.4 g of intermediate 8:

[0203] d) A mixture of 500 mg intermediate 8 and 70 mgN,N-dimethylethylenediamine in p-xylene was heated to 110° C. for 3hours. After evaporation of the solvent and purfication with columnchromatography 181 mg of intermediate 9 was obtained:

[0204] e) Debenzylation was performed with Pd/C and H₂ to affordintermediate 10.

[0205] f) To a mixture of 95 mg intermediate 10 and 27 mg triethylaminein dichloromethane was added 51 mg1-[[[[(3R,3aS,6aR)-hexahydroftiro[2,3-b]furan-3-yl]oxy]carbonyl]-oxy]-2,5-pyrrolidinedione(described in W09967417). This mixture is stirred at room temperaturefor 12 hours. After evaporation of dichloromethane under reducedpressure, the crude product is purified on silica, yielding 83 mg ofcompound 2 (70%).

[0206] In an analogous way, compounds 4, 6, 7 and 8 were prepared.

EXAMPLE 5

[0207] Synthesis of Compound 10

[0208] 0.23 g of isonicotinic acid, 0.36 g of EDC and 12 mg of HOBT weremixed and added to 1 g of the 2-aminobenzoxazole intermediate 11 in 40ml of dichloromethane. The mixture was stirred under an inert atmosphereof nitrogen at room temperature for 48 h. 50 ml of water was added thewater layer was extracted with dichloromethane and the combined organiclayers were washed with brine, dried under MgSO₄ and the solvent wasevaporated under reduced pressure. Purification was performed on silicayielding 0.57 g (48%) of compound 10.

EXAMPLE 6

[0209]

[0210] A mixture of 2.5 g 2-aminophenol (6-1) and 20 ml ethyl acetatewas heated to 45° C. 3 g of cyanogen bromide was added to the mixture.The mixture was stirred at 45-50° C. for hours. After cooling to roomtemperature, 1.5 g of podium hydroxide in 15 ml of water was added. Theorganic layer was separated and washed with brine until neutral pH.Toluene (5 ml) was added and the solvent was removed to yield 2.71 g(88%) 2-aminobenzoxazol (6-2).

[0211] 7.5 ml of chlorosulfonic acid was stirred at room temperatureunder an inert atmosphere. 5 g of 2-aminobenzoxazol (6-2) was added insmall portions. The temperature was kept between 30-60° C. during theaddition of 6-2. The mixture was heated to 80° C. for 2 hours. 5.3 g ofthionyl chloride was added drop wise, keeping the temperature at 65° C.The mixture was stirred during 2 hours. After cooling to 0° C. 10 ml ofethyl acetate and 10 ml of a solution of sodium carbonate (IN) wereadded. The organic layer was separated from the water layer and thislatter was extracted with ethyl acetate. The combined organic layerswere dried over calcium chloride, yielding 7.8 g (90%) of2-amino-6-chlorosulfonylbenzoxazole (63).

EXAMPLE 7

[0212]

[0213] A mixture of 1 g of sodium methoxide and 100 ml of toluene wasstirred at 0° C. under nitrogen atmosphere. A mixture of 1.9 g of methylchloracetate (7-1) and 1.1 g of methylformate was added drop wisekeeping the temperature between 5-10° C. The mixture was stirred for 2hours at 0° C. After washing with water., the organic layer was driedand evaporated under reduced pressure yielding 2-chloro-3-oxo-propionicacid methyl ester (7-2).

[0214] A mixture of 2.4 g of 2-chloro-3-oxo-propionic acid methyl ester(7-2), water 20 ml and 1.75 g of thiourea was refluxed for 2 hours. Themixture was cooled to room temperature and 0.25 g of norit was added andfiltered. A solution of 2.5N sodium hydroxide was added to the filtrateuntil neutral pH. The filtration yielded 1.23 g (44%) of2-aminothiazole-5-carboxylic acid methyl ester (7-3).

[0215] The mixture of 2.15 g of isoamyl nitrite and 10 ml of dioxane wasstirred at 80° C. under la nitrogen atmosphere. A solution of 1.23 g of2-aminothiazole-5-carboxylic acid methyl ester (7-3) in 20 ml of dioxanewas added drop wise. The mixture was refluxed for 2 hours. After coolingto room temperature 30 ml of ethyl acetate was added. The mixture waswashed with brine and dried and the solvent evaporated under reducedpressure. The crude product is purified on silica, thus yielding 0.54 g(48%) of thiazol 5-carboxylic acid methyl ester (7-4).

[0216] A mixture of 0.54 g of thiazol 5-carboxylic acid methyl ester(g-4) and 10 ml tetrahydrofurane (THF) was stirred at 0° C. under anitrogen atmosphere. The mixture of 0.16 g of lithium aluminium hydrideand 5 ml of ether was added drop wise. After 1 hour at 0° C. water and20% sodium hydroxide were added, and stirred during 30 minutes (min).The mixture was filtered over decalite and the solvent was removed byazeotropique distillation with toluene yielding 0.3 g (69%) ofthiazol-5-yl-methanol (7-5).

EXAMPLE 8

[0217] A mixture of 1.15 g of thiazol-5-yl-methanol (8-1) and 1.2 gtriethylamine (TEA) in 25 ml of dichloromethane (DCM) was stirred atroom temperature under an atmosphere of nitrogen. 2.56 g ofN,N′-disuccinimidyl carbonate was then added and the resulting mixturewas stirred for 10-15 minutes. The solution was stirred for anadditional 2 hours. The resulting intermediate (8-2) was used directlyin the subsequent reaction with the amine (8-3). Instead of amines alsosalts thereof can be used.

[0218] Triethylamine 2 g and the amine 5 g (8-3) were added todichloromethane 40 ml and the resulting mixture was stirred at roomtemperature. Subsequently, a portion of the solution comprising 8-2 wasadded drop wise. The reaction mixture was stirred at room temperaturefor 2 hours. The reaction mixture was washed with water and then driedto yield compound (8-4). TABLE 1 Compounds of the present inventionprepared according to the methods described above. If no stereochemistryis indicated, the compound is present as a racemic mixture.

Compound N° R_(a) R_(b) Synthesis 1

—NHC(═O)CH₃ A 2

—NHCH₂CH₂N(CH₃)₂ B 3

—NHC(═O)OCH₂CH₃ A 4

B 5

—NHC(═O)OCH₂CH₃ A 6

—NHCH₂CH₂OH B 7

B 8

B 9

—NHC(═O)OCH₃ A 10

F 11

—NHC(═O)CH₃ F 12

—NHC(═O)OCH₂CH₃ A 13

F 14

F 15

F 16

F 17

F 18

F 19

—NHC(═O)CH₂N(CH₃)₂ B 20

B 21

B 22

B 23

B 24

C 25

C 26

F 27

F 28

F 29

F 30

F 31

F 32

F 33

F 34

F 35

F 36

B 37

F

[0219] Antiviral Analyses:

[0220] The compounds of the present invention were examined foranti-viral activity in a cellular assay. The assay demonstrated thatthese compounds exhibited potent anti-HIV activity against a wild typelaboratory HIV strain (HIV-1 strain LAI). The cellular assay wasperformed according to the following procedure.

[0221] Cellular Assay Experimental Method:

[0222] HIV- or mock-infected MT4 cells were incubated for five days inthe presence of various concentrations of the inhibitor. At the end ofthe incubation period, all HIV-infected cells have been killed by thereplicating virus in the control cultures in the absence of anyinhibitor. Cell viability is measured by measuring the concentration ofMTT, a yellow, water soluble tetrazolium dye that is converted to apurple, water insoluble formazan in the mitochondria of living cellsonly. Upon solubilization of the resulting formazan crystals withisopropanol, the absorbance of the solution is monitored at 540 nm. Thevalues correlate directly to the number of living cells remaining in theculture at the completion of the five day incubation. The inhibitoryactivity of the compound was monitored on the virus-infected cells andwas expressed as EC₅₀ and EC₉₀. These values represent the amount of thecompound required to protect 50% and 90%, respectively, of the cellsfrom the cytopathogenic effect of the virus. The toxicity of thecompound was measured on the mock-infected cells and was expressed asCC₅₀, which represents the concentration of compound required to inhibitthe growth of the cells by 50%. The selectivity index (SI) (ratioCC₅₀/EC₅₀) is an indication of the selectivity of the anti-HIV activityof the inhibitor. Wherever results are reported as e.g. pEC₅₀ or pCC₅₀values, the result is expressed as the negative logarithm of the resultexpressed as EC₅₀ or CC₅₀ respectively.

[0223] Antiviral Spectrum:

[0224] Because of the increasing emergence of drug resistant HIVstrains, the present compounds were tested for their potency againstclinically isolated HIV strains harboring several mutations (Table 2 and3). These mutations are associated with resistance to proteaseinhibitors and result in viruses that show various degrees of phenotypiccross-resistance to the currently commercially available drugs such asfor instance saquinavir, ritonavir, nelfinavir, indinavir andamprenavir. TABLE 2 List of mutations present in the protease gene ofthe HIV strains (A to F) used. A V003I, L010I, V032T, L033M, E035D,S037Y, S037D, M046I, R057R/K, Q058E, L063P, K070T, A071V, I072V, I084V,L089V B V003I, L010I, K020R, E035D, M036I, S037N, Q058E, I062V, L063P,A071V, I072M, G073S, V077I, I084V, I085V, L090M C V003I, L010I, I015V,L019I, K020M, S037N, R041K, I054V, Q058E, L063P, A071V, I084V, L090M,I093L D V0031, L010L/I, I013V, L033I, E035D, M036I, M046L, K055R, R057K,L063P, I066F, A071V, I084V, N088D, L090M E V003I, L010I, V011I, A022V,L024I, E035D, M036I, S037T, R041K, I054V, I062V, L063P, A071V, I084V FL010F, M046I, M071V, I084V

[0225] Results:

[0226] As a measure of the broad spectrum activity of the presentcompounds, the fold resistance (FR), defined as FR=EC₅₀(mutantstrain)/EC₅₀(HIV-1 strain LA]), was determined. Table 3 shows theresults of the antiviral testing in terms of fold resistance. As can beseen in this table, the present compounds are effective in inhibiting abroad range of mutant strains: Column A FR value towards mutant A,Column B: FR towards mutant B , Column C: FR towards mutant C, Column D:FR towards mutant D, Column E: FR towards mutant E, Column F: FR towardsmutant F. The toxicity is expressed as the pCC₅₀ value as determinedwith mock transfected cells. TABLE 3 Results of the toxicity testing andthe resistance testing against strain A to F (expressed as FR). NDindicates not determined Comp. N° Tox A (FR) B (FR) C (FR) D (FR) E (FR)F (FR) 1 <4 0.63 0.80 0.50 0.72 0.40 0.71 2 <4 1.1 0.49 0.59 0.32 0.362.7 3 4.24 0.74 0.66 0.59 0.40 0.35 1.1 4 ND 1.95 1.62 1.70 0.47 0.503.2 5 5.04 3.1 1.1 2.63 2.1 1.64 16 7 4.49 13 ND 0.70 ND 2.3 30 8 <4 305.8 1.7 5.8 ND 58 9 <4 3.5 1.2 1.2 2.7 3.6 14.5 10 4.27 3.9 10.83 1.13.9 1.3 20 11 <4 42 2.1 2.5 10 4.8 74 12 <4 8.5 1.4 2.5 4.8 2.5 15 13 <42.3 0.75 0.64 0.91 0.91 5.2 14 5.03 5.2 3.8 3.1 3.7 3.1 19 15 <4 2.30.81 1.1 1.7 1.5 7.8 16 4.25 3.5 0.72 0.69 3.3 1.1 17 17 <4 3.1 0.790.91 3.1 1.7 13 18 4.24 2.6 0.85 1.5 3.0 2.6 13 19 <4 3.0 0.81 0.91 2.2ND 17 24 <4 1.9 0.53 1.3 1.6 1.4 6.8 25 4.31 3.9 1.3 3.0 3.9 3.9 18 264.14 9.3 2.45 3.4 15 11 59 27 <4 4.4 1.00 0.68 2.9 0.85 24 28 <4 4.40.89 0.51 2.9 1.9 23 29 <4 8.1 1.4 0.79 4.9 0.87 39 30 <4 ND ND ND ND NDND 31 <4 9.5 1.3 1.25 7.6 ND 33 32 <4 8.3 1.7 1.1 8.1 ND 42 34 4.25 7.21.4 1.7 5.8 2.3 25 35 4.26 13 2.3 1.1 3.5 ND 48

[0227] Biovailability:

[0228] Caco-2 Permeability Assay for Intestinal Absorption

[0229] The permeability of different compounds is evaluated according toa Caco-2 test protocol as described by Augustijns et al. (Augustijns etal. (1998). Int. J. of Pharm, 166, 45-54) whereby, Caco-2 cells at cellpassage number between 32 and 45 are grown in 24-well transwell cellculture plates for 21 to 25 days. The integrity of the cell monolayer ischecked by measuring the transepithelial electrical resistance (TEER).The test is performed at pH 7.4 and at 100 μM donor compoundconcentration.

[0230] Aqueous Solubility at Different pH Levels

[0231] The equilibrium solubility in simulated gastrointestinalsolutions under thermodynamic conditions is a good measure for thesolubility profile of the compound in the stomach and the differentparts of the intestine. Simulated gastric fluid (SGF) (without pepsin)is set at pH of 1.5. Simulated intestinal fluids (SIF) (without bilesalts) are set at pH 5, pH 6.5, pH 7 and pH 7.5. The experimentalprotocol uses 96-well flat-bottom microplates in which 1 mg of compoundis added per well (stock solution in methanol) and evaporated todryness. The compounds are resolubilized in SGF and SIF and incubatedovernight on a horizontal shaking device at 37° C. After filtration, thecompound concentrations are determined by UV-spectrophotometry.

[0232] Oral availability in the rat

[0233] The compounds are formulated as a 20 mg/ml solution or suspensionin DMSO, PEG400 or cyclodextin 40% in water. For most experiments in therat (male and female rats), three dosing groups are formed: 1/singleintraperitoneal (IP) dose at 20 mg/kg using the DMSO formulation;2/single oral dose at 20 mg/kg using the PEG400 formulation and 3/singleoral dose at 20 mg/kg using the cyclodextrin formulation. Blood issampled at regular time intervals after dosing and drug concentrationsin the serum are determined using a LC-MS bioanalytical method. Serumconcentrations are expressed in ng/mg after normalization to 10 mg/kg.Serum concentration at 30 minutes (30′) and at 3 hours (180′) can bedetermined as these values reflect the extent of absorption (30′) andthe speed of elimination (180′). The rat serum concentration at 9 minand 180 min following IP administration of 20 mg/kg of compound 4 are1098 ng/ml and 553 ng/ml respectively.

[0234] Boosting the Systemic Bioavailability

[0235] With the described type of compounds (protease-inhibitors), it isknown that inhibition of the metabolic degradation processes canmarkedly increase the systemic availability by reducing the first-passmetabolism in the liver and the metabolic clearance from the plasma.This ‘boosting’ principle can be applied in a clinical setting to thepharmacological action of the drug. This principle can be also exploredboth in the rat or the dog by simultaneous administration of a compoundthat inhibits the Cyt-p450 metabolic enzymes, Known blockers are forexample ritonavir and ketoconazole. Dosing a single oral dose ofritonvir at 5 mg/kg in the rat and the dog may result in an increase ofthe systemic availability.

[0236] Protein Binding Analyses:

[0237] Human serum proteins like albumin (HSA) or α-1 acid glycoprotein(AAG) are known to bind many drugs, resulting in a possible decrease inthe effectiveness of those compounds. In order to determine whether thepresent compounds would be adversely affected by this binding, theanti-HIV activity of the compounds was measured in the presence of humanserum, thus evaluating the effect of the binding of the proteaseinhibitors to those proteins.

[0238] MT4 cells are infected with HIV-1 LAI at a multiplicity ofinfection (MOI) of 0.001-0.01 CC₅₀ (50% cell culture infective dose percell, CCID₅₀). After 1 h incubation, cells are washed and plated into a96 well plate containing serial dilutions of the compound in thepresence of 10% FCS (foetal calf serum), 10% FCS+1 mg/ml AAG (α₁-acidglycoprotein), 10% FCS+45 mg/ml HSA (human serum albumin) or 50% humanserum (HS). After 5 or 6 days incubation, the EC₅₀ (50% effectiveconcentration in cell-based assays) is calculated by determining thecell viability or by quantifying the level of HIV replication. Cellviability is measured using the assay described above. Into a 96 wellplate containing serial dilutions of the compound in the presence of 10%FCS or 10% FCS +1 mg/ml AAG, HIV (wild type or resistant strain) and MT4cells are added to a final concentration of 200-250 CC₅₀/well and 30,000cells/well, respectively. After 5 days of incubation (37° C., 5% CO₂),the viability of the cells is determined by the tetrazolium colorimetricMTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumdiphenyltetrazolium bromide) method (Pauwels et al. J Virol. Methods1988, 20, 309-321). TABLE 4 Effect of the protein binding on the invitro activity of compound 1 Ratio of the EC₅₀ compared to FCS (10%)Compound name FCS(10%) AAG 1 mg/ml HSA 45 mg/ml HS 50% Compound 1 1 25 615

1. A compound having the formula

an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, esteror metabolite thereof, wherein R₁ and R₈ are, each independently,hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, arylC₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₆alkyl, aryl, Het¹, Het¹C₁₋₆alkyl, Het², Het²C₁₋₆alkyl;R₁ may also be a radical of formula

 wherein R₉, R_(10a) and R_(10b) are, each independently, hydrogen,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl orC₁₋₄alkyl optionally substituted with aryl, Het¹, Het², C₃₋₇cycloalkyl,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(O)_(t), hydroxy,cyano, halogen or amino optionally mono- or disubstituted where thesubstituents are each independently selected from C₁₋₄alkyl, aryl,arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het²,Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl; whereby R₉, R_(10a) and the carbonatoms to which they are attached may also form a C₃₋₇cycloalkyl radical;when L is —O—C₁₋₆alkanediyl-C(═O)— or —NR₈—C₁₋₆alkanediyl-C(═O)—, thenR₉ may also be oxo; R_(11a) is hydrogen, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₇cycloalkyl, aryl, aminocarbonyl optionally mono- or disubstituted,aminoC₁₋₄alkylcarbonyloxy optionally mono- or disubstituted,C₁₋₄alkyloxycarbonyl, aryloxycarbonyl, Het¹oxycarbonyl, Het²oxycarbonyl,aryloxycarbonylC₁₋₄alkyl, arylC₁₋₄alkyloxycarbonyl, C₁₋₄alkylcarbonyl,C₃₋₇cycloalkylcarbonyl, C₃₋₇cycloalkyl-C₁₋₄alkyloxycarbonyl,C₃₋₇cycloalkylcarbonyloxy, carboxylC₁₋₄alkylcarbonyloxy,C₁₋₄alkylcarbonyloxy, arylC₁₋₄alkylcarbonyloxy, arylcarbonyloxy,aryloxycarbonyloxy, Het¹carbonyl, Het¹carbonyloxy,Het¹C₁₋₄alkyloxycarbonyl, Het²carbonyloxy, Het²C₁₋₄alkylcarbonyloxy,Het²C₁₋₄alkyloxycarbonyloxy or C₁₋₄alkyl optionally substituted witharyl, aryloxy, Het², halogen or hydroxy; wherein the substituents on theamino groups are each independently selected from C₁₋₄alkyl, aryl,arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het²,Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl; R_(11b) is hydrogen, C₃₋₇cycloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, Het¹, Het² or C₁₋₄alkyl optionallysubstituted with halogen, hydroxy, C₁₋₄alkylS(═O)_(t), aryl,C₃₋₇cycloalkyl, Het¹, Het², amino optionally mono- or disubstitutedwhere the substituents are each independently selected from C₁₋₄alkyl,aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹,Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl; whereby R_(11b) may be linked tothe remainder of the molecule via a sulfonyl group; each independently,t is zero, 1 or 2; R₂ is hydrogen or C₁₋₆alkyl; L is —C(═O)—, —O—C(═O)—,—NR₈—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—, —NR₈—C₁₋₆alkanediyl-C(═O)—,—S(═O)₂—, —O—S(═O)₂—, —NR₈—S(═O)₂ whereby either the C(═O) group or theS(═O)₂ group is attached to the NR₂ moiety; whereby the C₁₋₆alkanediylmoiety is optionally substituted with aryl, Het¹ or Het^(2;) R₃ isC₁₋₆alkyl, aryl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, orarylC₁₋₄alkyl; R₄ is hydrogen, C₁₋₄alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, or C₁₋₆alkyl optionally substituted with oneor more substituents each independently selected from aryl, Het¹, Het²,C₃₋₇cycloalkyl, C₁₋₄alkloxycaronyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(═O)_(t), hydroxy,cyano, halogen and amino optionally mono- or disubstituted where thesubstituents are each independently selected from C₁₋₄alkyl, aryl,arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het²,Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl; A is C₁₋₆alkanediyl, —C(═O)—, —C(═S)—,—S(═O)₂—, C₁₋₆alkanediyl-C(═O)—, C₁₋₆alkanediyl-C(═S)— orC₁₋₆alkanediyl-S(═O)₂—; whereby the point of attachment to the nitrogenatom is the C₁₋₆alkanediyl group in those moieties containing saidgroup; R₅ is hydrogen, hydroxy, C₁₋₆alkyl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,aminoC₁₋₆alkyl whereby the amino group may optionally be mono- ordi-substituted with C₁₋₄alkyl; R₆ is C₁₋₆alkyloxy, Het¹, Het¹oxy, Het²,Het²oxy, aryl, aryloxy or amino; and in case -A- is other thanC₁₋₆alkanediyl then R₆ may also be C₁₋₆alkyl, Het¹C₁₋₄alkyl,Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl, Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₆alkyl; whereby each of the amino groups inthe definition of R₆ may optionally be substituted with one or moresubstituents each independently selected from C₁₋₄alkyl,C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, aryl, arylcarbonyl,aryloxycarbonyl, Het¹, Het², arylC₁₋₄alkyl, Het¹C₁₋₄alkyl orHet²C₁₋₄alkyl; and -A-R( may also be hydroxyC₁₋₆alkyl; R₅ and -A-R₆taken together with the nitrogen atom to which they are attached mayalso form Het¹ or Het².
 2. A compound according to claim 1, wherein: R₉,R_(10a) and R_(10b) are, each independently, hydrogen,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl orC₁₋₄alkyl optionally substituted with aryl, Het¹, Het², C₃₋₇cycloalkyl,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(O)_(t), hydroxy,cyano, halogen or amino optionally mono- or disubstituted where thesubstituents are selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl; whereby R₉, R_(10a) and the carbon atoms to which theyare attached may also form a C₃₋₇cycloalkyl radical; R_(11a) ishydrogen, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, aryl, aminocarbonyloptionally mono- or disubstituted, aminoC₁₋₄alkylcarbonyloxy optionallymono- or disubstituted, C₁₋₄alkyloxycarbonyl, aryloxycarbonyl,Het¹oxycarbonyl, Het²oxycarbonyl, aryloxycarbonylC₁₋₄alkyl,arylC₁₋₄alkyloxycarbonyl, C₁₋₄alkylcarbonyl, C₃₋₇cycloalkylcarbonyl,C₃₋₇cycloalkylC₁₋₄alkyloxycarbonyl, C₃₋₇cycloalkylcarbonyloxy,carboxylC₁₋₄alkylcarbonyloxy, C₁₋₄alkylcarbonyloxy,arylC₁₋₄alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy,Het¹carbonyl, Het¹carbonyloxy, Het¹C₁₋₄alkyloxycarbonyl,Het²carbonyloxy, Het²C₁₋₄alkylcarbonyloxy, Het²C₁₋₄alkyloxycarbonyloxyor C₁₋₄alkyl optionally substituted with aryl, aryloxy, Het² or hydroxy;wherein the substituents on the amino groups are each independentlyselected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl;R_(11b) is hydrogen, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl,Het¹, Het² or C₁₋₄alkyl optionally substituted with halogen, hydroxy,C₁₋₄alkylS(═O)_(t), aryl, C₃₋₇cycloalkyl, Het¹, Het², amino optionallymono- or disubstituted where the substituents are selected fromC₁₋₄alkyl, aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl,Het¹, Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl; whereby R_(11b) may belinked to the remainder of the molecule via a sulfonyl group; t is zero,1 or 2; L is —C(═O)—, —O—C(═O)—, —NR₈—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—,—NR₈—C₁₋₆alkanediyl-C(═O)—, —S(═O)₂—, —O—S(═O)₂—, —NR₈—S(═O)₂ wherebyeither the C(═O) group or the S(═O)₂ group is attached to the NR₂moiety; R₄ is hydrogen, C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, or C₁₋₆alkyl optionally substituted with one or moresubstituents selected from aryl, Het¹, Het², C₃₋₇cycloalkyl,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(═O)_(t), hydroxy,cyano, halogen and amino optionally mono- or disubstituted where thesubstituents are selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl; R₆ is C₁₋₆alkyloxy, Het¹, Het¹oxy, Het², Het²oxy, aryl,aryloxy or amino; and in case -A- is other than C₁₋₆alkanediyl then Rmay also be C₁₋₆alkyl, Het¹C₁₋₄alkyl, Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl,Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl, aryloxyC₁₋₄alkyl or aminoC₁₋₆alkyl;whereby each of the amino groups in the definition of R₆ may optionallybe substituted with one or more substituents selected from C₁₋₄alkyl,C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, aryl, arylcarbonyl,aryloxycarbonyl, Het¹, Het², arylC₁₋₄alkyl, Het¹C₁₋₄alkyl orHet²C₁₋₄alkyl.
 3. A compound according to any of claim 1 to 2 wherein R₁is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl arylC₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkyl-C₁₋₆alkyl, aryl, Het¹, Het¹C₁₋₆alkyl, Het² orHet²C₁₋₆alkyl; wherein Het¹ is a saturated or partially unsaturatedmonocyclic heterocycle having 5 or 6 ring members, which contains one ormore heteroatom ring members each independently selected from nitrogen,oxygen or sulfur and which is optionally substituted on one or morecarbon atoms.
 4. A compound according to any of claims 1 to 3 wherein Lis —O—C₁₋₆alkanediyl-C(═O)—.
 5. A compound according to any one ofclaims 1 to 4 wherein A is C₁₋₆alkanediyl, —C(═O)— orC₁₋₆alkanediyl-C(═O)—; whereby the point of attachment to the nitrogenatom is the C₁₋₆alkanediyl group in those moieties containing saidgroup; R₅ is hydrogen, C₁₋₆alkyl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,aminoC₁₋₆alkyl whereby the amino group may optionally be mono- ordi-substituted with C₁₋₄alkyl; and in case -A- is —C(═O)-then R₆ isC₁₋₆alkyloxy, Het¹, Het¹oxy or Het²oxy, aryl, Het¹C₁₋₄alkyl,Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl, Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl; and in case -A- is C₁₋₆alkanediylthen R₆ is amino, C₁₋₆alkyloxy, Het¹, Het¹oxy or Het²oxy; and in case-A- is C₁₋₆alkanediyl-C(═O)-then R₆ is C₁₋₆alkyloxy, Het¹, Het¹oxy orHet²oxy, aryl, C₁₋₆alkyl, Het¹C₁₋₄alkyl, Het¹oxyC₁₋₄alkyl,Het²C₁₋₄alkyl, Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl, aryloxyC₁₋₄alkyl oraminoC₁₋₄alkyl; whereby each of the amino groups in the definition of R₆may optionally be substituted with one or more substituents selectedfrom C₁₋₄alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, aryl,arylcarbonyl, aryloxycarbonyl, Het¹, Het², arylC₁₋₄alkyl, Het¹C₁₋₄alkylor Het²C₁₋₄alkyl; and R₅ and -A-R₆ taken together with the nitrogen atomto which they are attached may also form Het¹ whereby Het¹ issubstituted by at least an oxo group.
 6. A compound according to any ofclaims 1 to 3, wherein R₁ is Het² or Het²C₁₋₆alkyl; wherein said Het² isan aromatic heterocycle having at least one heteroatom eachindependently selected from nitrogen, oxygen and sulfur; and L is—C(═O)—, —O—C(═O)— or —O—C₁₋₆alkyl-C(═O)—.
 7. A compound according toany of claims 1 to 3, wherein R₁ is Het² or Het²C₁₋₆alkyl; wherein saidHet² is an aromatic heterocycle having at least two heteroatom eachindependently selected from nitrogen, oxygen and sulfur; and L is—C(═O)—, —O—C(═O)— or —O—C₁₋₆alkyl-C(═O)—.
 8. A compound according toany of claims 1 to 4, wherein A is C₁₋₆alkanediyl or —C(═O)—; R₅ ishydrogen or methyl; and R₆ is C₁₋₆alkyloxy, Het¹, Het², amino or aminoC₁₋₆alkyl; whereby each amino optionally may be mono- or disubstitutedwhere the substituents are each independently selected from C₁₋₄alkyl,aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹,Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl.
 9. A compound according to any ofclaims 1 to 3, wherein R₁ is Het² or Het²C₁₋₆alkyl; wherein said Het² isan aromatic heterocycle having at least one heteroatom eachindependently selected from nitrogen, oxygen and sulfur; L is —C(═O)—,—O—C(═O)— or —O—C₁₋₆alkyl-C(═O)—; A is C₁₋₆alkanediyl or —C(═O)—; R₅ ishydrogen or methyl; and R₆ is C₁₋₆alkyloxy, Het¹, Het², amino or aminoC₁₋₆alkyl; whereby each amino optionally may be mono- or disubstituted,where the substituents are each independently selected from C₁₋₄alkyl,aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹,Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl.
 10. A compound according to anyof claims 1 to 3, wherein, R₁ is 2-thiazolylmethyl-; and L is —O—C(═O)—.11. A compound according to any of claims 1 to 3, wherein R₅ ishydrogen; A is —C(═O)—; and R₆ is Het²; wherein said Het² contains 5 or6 ring members and one heteroatom selected from nitrogen, oxygen orsulfur.
 12. A compound according to any of claims 1 to 3, wherein R₁ isHet¹, having 8 ring members and two heteroatoms each independentlyselected from nitrogen, oxygen or sulfur; L is —O—C(═O)—; R₅ is hydrogenor methyl; A is —C(═O)— or C₁₋₆alkanediyl; and R₆ is optionally mono- ordisubstituted aminoC₁₋₄alkyl, Het¹, Het²; wherein said Het² contains 5or 6 ring members and one heteroatom selected from nitrogen, oxygen orsulfur; wherein the amino substituents are each independently selectedfrom C₁₋₄alkyl, aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl.13. A compound as claimed in any one of claim 1 to 12 in a prodrug form.14. A compound as claimed in any one of claim 1 to 12 in apharmaceutically tolerable salt form.
 15. A pharmaceutical composition,comprising an effective amount of at least one compound as claimed inany one of claims 1 to 14, and a pharmaceutically tolerable excipient.16. A compound as claimed in any one of claims 1 to 14 for use as amedicine.
 17. A method of inhibiting a protease of a retrovirus in amammal infected with said retrovirus, comprising a protease inhibitingamount of a compound according to any one of claims 1 to 14 to saidmammal in need thereof.
 18. A method of treating or combating infectionor disease associated with retrovirus infection in a mammal, comprisingadministering an effective amount of at least one compound according toany one of claims 1 to 14 to said mammal.
 19. The methods of claim 17 or18, wherein said mammal is a human.
 20. A method of inhibitingretroviral replication, comprising contacting a retrovirus with aneffective amount of at least one compound according to any one of claims1 to
 14. 21. The method of claim 17 or 18 or 19, wherein the retrovirusis a human immunodeficiency virus (HIV).
 22. The method as claimed inclaim 21, wherein the HIV virus is a multi-drug resistant strain.
 23. Acompound as claimed in any one of claims 1 to 14 for use as a medecine.24. The use of a compound as claimed in any one of claims 1 to 14 in themanufacture of a medicament for treating or combating infection ordisease associated with retrovirus infection in a mammal.
 25. The use ofa compound as claimed in any one of claims 1 to 14 in the manufacture ofa medicament for inhibiting a protease of a retrovirus in a mammalinfected with said retrovirus.
 26. The use of a compound as claimed inany one of claims 1 to 14 in the manufacture of a medicament forinhibiting retroviral replication.
 27. The use of a compound as claimedin any one of claims 24 to 26 wherein the retrovirus is a humanimmunodeficiency virus (HIV).
 28. The use of a compound as claimed inany one of claims 24 to 26 wherein the retrovirus is a multi-drugresistant strain.